Chemokine receptor modulators and uses thereof

ABSTRACT

Disclosed herein, inter alia, are compounds and methods of use thereof for the modulation of CCR4 activity.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/662,861 filed Jul. 28, 2017, now allowed, and claims the benefit ofpriority under 35 U.S.C. § 119(e) of U.S. Provisional Application No.62/368,848, filed Jul. 29, 2016 and U.S. Provisional Application No.62/426,087, filed Nov. 23, 2016. The disclosure of each of the priorapplications is considered part of and is incorporated by reference inthe disclosure of this application in their entirities and for allpurposes.

BACKGROUND

The successful operation of the host defense system is the result ofseveral processes that work together to eliminate foreign pathogens.Coordinated innate and acquired immune responses are required, and manysecreted and cell-associated factors have been identified as importantmediators coordinating and regulating these two arms of host defense.Chemokines are a family of cytokines that act as chemoattractants toguide leukocyte migration. They are secreted by a wide variety of cellsand can be functionally divided into two groups, hemostatic chemokinesand inflammatory chemokines. Hemostatic chemokines are constituentlyproduced in certain tissues and control cells of the immune systemduring processes of immune surveillance, such as directing lymphocytesto the lymph nodes to allow them to screen for invasion of pathogens.Inflammatory chemokines are released from cells in response to apathological event (e.g., pro-inflammatory stimuli such as IL-1 orviruses). They function primarily as chemoattractants as part of theinflammatory response and serve to guide cells of both the innate andadaptive immune systems to the site of inflammation. The C—C chemokinereceptor type 4 (CCR4), plays a role in the progression of a number ofinflammation-related and other disorders. The identification ofcompounds that modulate CCR4 function is an ongoing challenge. Disclosedherein, inter alia, are solutions to these and other problems in theart.

BRIEF SUMMARY OF THE INVENTION

In an aspect provided herein, is a compound having structural Formula(I):

or a pharmaceutically acceptable salt thereof. X¹ is CR⁸ or N. X² is CR⁹or N. X³ is CR¹⁰ or N. The symbols n1, n2, n3, n4, n5, n6, n7, n8, n9and n10 are independently an integer from 0 to 4. The symbol z3 is aninteger from 0 to 11. In embodiments, z3 is independently an integerfrom 0 to 4. The symbols m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, v1,v2, v3, v4, v5, v6, v7, v8, v9 and v10 are independently 1 or 2. Thesymbol z1 is an integer from 0 to 5. The symbol z2 is an integer from 0to 4. In embodiments, z2 is an integer from 0 to 2. The symbol z4 is aninteger from 0 to 2. L⁷ is a bond, —O—, —S—, —NR^(7.2B)—, —C(O)—,—C(O)O—, —S(O)—, —S(O)₂—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene. R¹ is hydrogen, halogen,—CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1), —CN, —N₃, —SO_(n1)R^(1A),—SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C), —ONR^(1B)R^(1C),—NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C), —N(O)_(m1),—NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A),—NR^(1B)SO₂R^(1A), —NR^(1B)C(O)R^(1D), —NR^(1B)C(O)OR^(1D),—NR^(1B)OR^(1D), —OCX^(1.1) ₃, —OCHX^(1.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R² is hydrogen, halogen, —CX^(2.1) ₃,—CHX^(2.1) ₂, —CH₂X^(2.1), —CN, —N₃, —SO_(n2)R^(2A),—SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C), —ONR^(2B)R^(2C),—NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C), —N(O)_(m2),—NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D), —C(O)NR^(2B)R^(2C), —OR^(2A),—NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D), —NR^(2B)C(O)OR^(2D),—NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R³ is independently hydrogen, halogen,—CX^(3.1) ₃, —CHX^(3.1) ₂, —CH₂X^(3.1), —CN, —N₃, —SO_(n3)R^(3A),—SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C), —ONR^(3B)R^(3C),—NHC(O)NHNR^(3B)R^(3C), —NHC(O)NR^(3B)R^(3C), —N(O)_(m3),—NR^(3B)R^(3C), —C(O)R^(3D), —C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A),—NR^(3B)SO₂R^(3A), —NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D),—NR^(3B)OR^(3D), —OCX^(3.1) ₃, —OCHX^(3.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl. R⁴ is hydrogen, halogen, —CX^(4.1) ₃,—CHX^(4.1) ₂, —CH₂X^(4.1), —CN, —N₃, —SO_(n4)R^(4A),—SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C), —ONR^(4B)R^(4C),—NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C), —N(O)_(m4),—NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D), —C(O)NR^(4B)R^(4C), —OR^(4A),—NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D), —NR^(4B)C(O)OR^(4D),—NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl. R⁵ is independently hydrogen, halogen, oxo,—CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —N₃, —SO_(n5)R^(5A),—SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), —ONR^(5B)R^(5C),—NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C), —N(O)_(m5),—NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A),—NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D),—NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl. R⁶ is independently hydrogen, halogen, oxo,—CX^(6.1) ₃, —CHX^(6.1) ₂, —CH₂X^(6.1), —CN, —N₃, —SO_(n6)R^(6A),—SO_(v6)NR^(6B)R^(6C), —NHNR^(6B)R^(6C), —ONR^(6B)R^(6C),—NHC(O)NHNR^(6B)R^(6C), —NHC(O)NR^(6B)R^(6C), —N(O)_(m6),—NR^(6B)R^(6C), —C(O)R^(6D), —C(O)OR^(6D), —C(O)NR^(6B)R^(6C), —OR^(6A),—NR^(6B)SO₂R^(6A), —NR^(6B)C(O)R^(6D), —NR^(6B)C(O)OR^(6D),—NR^(6B)OR^(6D), —OCX^(6.1) ₃, —OCHX^(6.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl. R⁷ is hydrogen, halogen, —CX^(7.1) ₃,—CHX^(7.1) ₂, —CH₂X^(7.1), —CN, —N₃, —SO_(n7)R^(7A),—SO_(v7)NR^(7B)R^(7C), —NHNR^(7B)R^(7C), —ONR^(7B)R^(7C),—NHC(O)NHNR^(7B)R^(7C), —NHC(O)NR^(7B)R^(7C), —N(O)_(m7),—NR^(7B)R^(7C), —C(O)R^(7D), —C(O)OR^(7D), —C(O)NR^(7B)R^(7C), —OR^(7A),—NR^(7B)SO₂R^(7A), —NR^(7B)C(O)R^(7D), —NR^(7B)C(O)OR^(7D),—NR^(7B)OR^(7D), —OCX^(7.1) ₃, —OCHX^(7.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl. R⁸ is hydrogen, halogen, —CX^(8.1) ₃,—CHX^(8.1) ₂, —CH₂X^(8.1), —CN, —N₃, —SO_(n8)R^(8A),—SO_(v8)NR^(8B)R^(8C), —NHNR^(8B)R^(8C), —ONR^(8B)R^(8C),—NHC(O)NHNR^(8B)R^(8C), —NHC(O)NR^(8B)R^(8C), —N(O)_(m8),—NR^(8B)R^(8C), —C(O)R^(8D), —C(O)OR^(8D), —C(O)NR^(8B)R^(8C), —OR^(8A),—NR^(8B)SO₂R^(8A), —NR^(8B)C(O)R^(8D), —NR^(8B)C(O)OR^(8D),—NR^(8B)OR^(8D), —OCX^(8.1) ₃, —OCHX^(8.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R⁹ is hydrogen, halogen, —CX^(9.1) ₃,—CHX^(9.1) ₂, —CH₂X^(9.1), —CN, —N₃, —SO_(n9)R^(9A),—SO_(v9)NR^(9B)R^(9C), —NHNR^(9B)R^(9C), —ONR^(9B)R^(9C),—NHC(O)NHNR^(9B)R^(9C), —NHC(O)NR^(9B)R^(9C), —N(O)_(m9),—NR^(9B)R^(9C), —C(O)R^(9D), —C(O)OR^(9D), —C(O)NR^(9B)R^(9C), —OR^(9A),—NR^(9B)SO₂R^(9A), —NR^(9B)C(O)R^(9D), —NR^(9B)C(O)OR^(9D),—NR^(9B)OR^(9D), —OCX^(9.1) ₃, —OCHX^(9.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R¹⁰ is hydrogen, halogen, —CX^(10.1) ₃,—CHX^(10.1) ₂, —CH₂X^(10.1), —CN, —N₃, —SO_(n10)R^(10A),—SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C), —ONR^(10B)R^(10C),—NHC(O)NHNR^(10B)R^(10C), —NHC(O)NR^(10B)R^(10C), —N(O)_(m10),—NR^(10B)R^(10C), —C(O)R^(10D), —C(O)OR^(10D), —C(O)NR^(10B)R^(10C),—OR^(10A), —NR^(10B)SO₂R^(10A), —NR^(10B)C(O)R^(10D),—NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D), —OCX^(10.1) ₃, —OCHX^(10.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R^(1A), R^(1B), R^(1C), R^(1D),R^(2A), R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(3C), R^(3D), R^(4A),R^(4B), R^(4C), R^(4D), R^(5A), R^(5B), R^(5C), R^(5D), R^(6A), R^(6B),R^(6C), R^(6D), R^(7A), R^(7B), R^(7C), R^(7D), R^(7.2B), R^(8A),R^(8B), R^(8C), R^(8D), R^(9A), R^(9B), R^(9C), R^(9D), R^(10A),R^(10B), R^(10C) and R^(10D) are independently hydrogen, halogen, —CF₃,—CCl₃, —CBr₃, —CI₃, —COOH, —CONH₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(1B), R^(1C), R^(2B), R^(2C), R^(3B), R^(3C), R^(4B), R^(4C), R^(5B),R^(5C), R^(6B), R^(6C), R^(7B), R^(7C), R^(8B), R^(8C), R^(9B), R^(9C),R^(10B) and R^(10C) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl. X^(1.1),X^(2.1), X^(3.1), X^(4.1), X^(5.1), X^(6.1), X^(7.1), X^(8.1), X^(9.1)and X^(10.1) are independently —Cl, —Br, —I or —F. At least one of X¹,X² and X³ is N.

In an aspect is provided a pharmaceutical composition, including acompound as described herein, including embodiments, or the structuralFormula (I), (II), (IIa), (IIb), (IIc), (IId), (III), (IV), (V), (VI),or (VII), and a pharmaceutically acceptable excipient.

In another aspect is provided a method of inhibiting C—C chemokinereceptor type 4 (CCR4), the method comprising contacting CCR4 with acompound as described herein, including embodiments, or the structuralFormula (I), (II), (IIa), (IIb), (IIc), (IId), (III), (IV), (V), (VI),or (VII) or a pharmaceutically acceptable salt thereof.

In an aspect, is provided a method of treating or preventing a diseaseor disorder mediated by CCR4, comprising administering to a subject inneed thereof a therapeutically effective amount of a compound asdescribed herein, including embodiments, or the structural Formula (I),(II), (IIa), (IIb), (IIc), (IId), (III), (IV), (V), (VI), or (VII) or apharmaceutically acceptable salt thereof.

In another aspect, provided herein is a kit including a compounddescribed herein (e.g., a CCR4 inhibitor) or pharmaceutical compositionsthereof. The kits are generally in the form of a physical structurehousing various components, as described below, and may be utilized, forexample, in practicing the methods described above.

DETAILED DESCRIPTION

Provided herein are, for example, compounds and compositions forinhibition of C—C chemokine receptor type 4, and pharmaceuticalcompositions comprising same. Also provided herein are, for example,methods of treating or preventing a disease, disorder or condition, or asymptom thereof, mediated by modulation (e.g., inhibition) of CCR4.

I. Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e., unbranched) or branchedcarbon chain (or carbon), or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include mono-, di- andmultivalent radicals, having the number of carbon atoms designated(i.e., C₁-C₁₀ means one to ten carbons). Alkyl is an uncyclized chain.Examples of saturated hydrocarbon radicals include, but are not limitedto, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl,isobutyl, sec-butyl, (cyclohexyl)methyl, homologs and isomers of, forexample, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Anunsaturated alkyl group is one having one or more double bonds or triplebonds. Examples of unsaturated alkyl groups include, but are not limitedto, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. An alkoxy is an alkylattached to the remainder of the molecule via an oxygen linker (—O—).

The term “alkylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkyl, asexemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (oralkylene) group will have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred herein. A “lower alkyl”or “lower alkylene” is a shorter chain alkyl or alkylene group,generally having eight or fewer carbon atoms. The term “alkenylene,” byitself or as part of another substituent, means, unless otherwisestated, a divalent radical derived from an alkene.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcombinations thereof, including at least one carbon atom and at leastone heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen andsulfur atoms may optionally be oxidized, and the nitrogen heteroatom mayoptionally be quaternized. The heteroatom(s) (e.g., N, S, Si, or P) maybe placed at any interior position of the heteroalkyl group or at theposition at which the alkyl group is attached to the remainder of themolecule. Heteroalkyl is an uncyclized chain. Examples include, but arenot limited to: —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃,—Si(CH₃)₃, —CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and—CN. Up to two or three heteroatoms may be consecutive, such as, forexample, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. A heteroalkyl moiety mayinclude one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moietymay include two optionally different heteroatoms (e.g., O, N, S, Si, orP). A heteroalkyl moiety may include three optionally differentheteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may includefour optionally different heteroatoms (e.g., O, N, S, Si, or P). Aheteroalkyl moiety may include five optionally different heteroatoms(e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8optionally different heteroatoms (e.g., O, N, S, Si, or P).

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, a divalent radical derivedfrom heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—. As describedabove, heteroalkyl groups, as used herein, include those groups that areattached to the remainder of the molecule through a heteroatom, such as—C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where“heteroalkyl” is recited, followed by recitations of specificheteroalkyl groups, such as —NR′R″ or the like, it will be understoodthat the terms heteroalkyl and —NR′R″ are not redundant or mutuallyexclusive. Rather, the specific heteroalkyl groups are recited to addclarity. Thus, the term “heteroalkyl” should not be interpreted hereinas excluding specific heteroalkyl groups, such as —NR′R″ or the like.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl andheterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, aheteroatom can occupy the position at which the heterocycle is attachedto the remainder of the molecule. Examples of cycloalkyl include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a“heterocycloalkylene,” alone or as part of another substituent, means adivalent radical derived from a cycloalkyl and heterocycloalkyl,respectively. “Cycloalkyl” is also meant to refer to bicyclic andpolycyclic hydrocarbon rings such as, for example,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “acyl” means, unless otherwise stated, —C(O)R where R is asubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent, which can be a single ring ormultiple rings (preferably from 1 to 3 rings) that are fused together(i.e., a fused ring aryl) or linked covalently. A fused ring aryl refersto multiple rings fused together wherein at least one of the fused ringsis an aryl ring. The term “heteroaryl” refers to aryl groups (or rings)that contain at least one heteroatom such as N, O, or S, wherein thenitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. Thus, the term “heteroaryl” includesfused ring heteroaryl groups (i.e., multiple rings fused togetherwherein at least one of the fused rings is a heteroaromatic ring). A5,6-fused ring heteroarylene refers to two rings fused together, whereinone ring has 5 members and the other ring has 6 members, and wherein atleast one ring is a heteroaryl ring. Likewise, a 6,6-fused ringheteroarylene refers to two rings fused together, wherein one ring has 6members and the other ring has 6 members, and wherein at least one ringis a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to tworings fused together, wherein one ring has 6 members and the other ringhas 5 members, and wherein at least one ring is a heteroaryl ring. Aheteroaryl group can be attached to the remainder of the moleculethrough a carbon or heteroatom. Non-limiting examples of aryl andheteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl,pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl,oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl,benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl,indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl,quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl,2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl,5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of the above notedaryl and heteroaryl ring systems are selected from the group ofacceptable substituents described below. An “arylene” and a“heteroarylene,” alone or as part of another substituent, mean adivalent radical derived from an aryl and heteroaryl, respectively. Aheteroaryl group substituent may be —O— bonded to a ring heteroatomnitrogen.

Spirocyclic rings are two or more rings wherein adjacent rings areattached through a single atom. The individual rings within spirocyclicrings may be identical or different. Individual rings in spirocyclicrings may be substituted or unsubstituted and may have differentsubstituents from other individual rings within a set of spirocyclicrings. Possible substituents for individual rings within spirocyclicrings are the possible substituents for the same ring when not part ofspirocyclic rings (e.g. substituents for cycloalkyl or heterocycloalkylrings). Spirocylic rings may be substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heterocycloalkylene andindividual rings within a spirocyclic ring group may be any of theimmediately previous list, including having all rings of one type (e.g.all rings being substituted heterocycloalkylene wherein each ring may bethe same or different substituted heterocycloalkylene). When referringto a spirocyclic ring system, heterocyclic spirocyclic rings means aspirocyclic rings wherein at least one ring is a heterocyclic ring andwherein each ring may be a different ring. When referring to aspirocyclic ring system, substituted spirocyclic rings means that atleast one ring is substituted and each substituent may optionally bedifferent.

The symbol “

” denotes the point of attachment of a chemical moiety to the remainderof a molecule or chemical formula.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

The term “alkylarylene” as an arylene moiety covalently bonded to analkylene moiety (also referred to herein as an alkylene linker). Inembodiments, the alkylarylene group has the formula:

An alkylarylene moiety may be substituted (e.g. with a substituentgroup) on the alkylene moiety or the arylene linker (e.g. at carbons 2,3, 4, or 6) with halogen, oxo, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂CH₃ —SO₃H, —OSO₃H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted C₁-C₅ alkyl orsubstituted or unsubstituted 2 to 5 membered heteroalkyl). Inembodiments, the alkylarylene is unsubstituted.

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “cycloalkyl,”“heterocycloalkyl,” “aryl,” and “heteroaryl”) includes both substitutedand unsubstituted forms of the indicated radical. Preferred substituentsfor each type of radical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R″′, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R″′, —NR″C(O)₂R′, —NR—C(NR′R″R″′)═NR″″,—NR—C(NR′R″)═NR″′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R″′,—ONR′R″, —NR′C(O)NR″NR″′R″″, —CN, —NO₂, —NR′SO₂R″, —NR′C(O)R″,—NR′C(O)—OR″, —NR′OR″, in a number ranging from zero to (2m′+1), wherem′ is the total number of carbon atoms in such radical. R, R′, R″, R″′,and R″″ each preferably independently refer to hydrogen, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl (e.g., aryl substituted with 1-3 halogens),substituted or unsubstituted heteroaryl, substituted or unsubstitutedalkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When acompound described herein includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, R″′,and R″″ group when more than one of these groups is present. When R′ andR″ are attached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example,—NR′R″ includes, but is not limited to, 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups including carbon atoms bound to groups other than hydrogengroups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R″′,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R″′, —NR″C(O)₂R′, —NR—C(NR′R″R″′)═NR″″, —NR—C(NR′R″)═NR″′,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R″′, —ONR′R″,—NR′C(O)NR″NR″′R″″, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy,and fluoro(C₁-C₄)alkyl, —NR′SO₂R″, —NR′C(O)R″, —NR′C(O)—OR″, —NR′OR″, ina number ranging from zero to the total number of open valences on thearomatic ring system; and where R′, R″, R″′, and R″″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl. When a compound described herein includes more than one Rgroup, for example, each of the R groups is independently selected asare each R′, R″, R″′, and R″″ groups when more than one of these groupsis present.

Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl,heteroaryl, cycloalkylene, heterocycloalkylene, arylene, orheteroarylene) may be depicted as substituents on the ring rather thanon a specific atom of a ring (commonly referred to as a floatingsubstituent). In such a case, the substituent may be attached to any ofthe ring atoms (obeying the rules of chemical valency) and in the caseof fused rings or spirocyclic rings, a substituent depicted asassociated with one member of the fused rings or spirocyclic rings (afloating substituent on a single ring), may be a substituent on any ofthe fused rings or spirocyclic rings (a floating substituent on multiplerings). When a substituent is attached to a ring, but not a specificatom (a floating substituent), and a subscript for the substituent is aninteger greater than one, the multiple substituents may be on the sameatom, same ring, different atoms, different fused rings, differentspirocyclic rings, and each substituent may optionally be different.Where a point of attachment of a ring to the remainder of a molecule isnot limited to a single atom (a floating substituent), the attachmentpoint may be any atom of the ring and in the case of a fused ring orspirocyclic ring, any atom of any of the fused rings or spirocyclicrings while obeying the rules of chemical valency. Where a ring, fusedrings, or spirocyclic rings contain one or more ring heteroatoms and thering, fused rings, or spirocyclic rings are shown with one more floatingsubstituents (including, but not limited to, points of attachment to theremainder of the molecule), the floating substituents may be bonded tothe heteroatoms. Where the ring heteroatoms are shown bound to one ormore hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and athird bond to a hydrogen) in the structure or formula with the floatingsubstituent, when the heteroatom is bonded to the floating substituent,the substituent will be understood to replace the hydrogen, whileobeying the rules of chemical valency.

Two or more substituents may optionally be joined to form aryl,heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-calledring-forming substituents are typically, though not necessarily, foundattached to a cyclic base structure. In one embodiment, the ring-formingsubstituents are attached to adjacent members of the base structure. Forexample, two ring-forming substituents attached to adjacent members of acyclic base structure create a fused ring structure. In anotherembodiment, the ring-forming substituents are attached to a singlemember of the base structure. For example, two ring-forming substituentsattached to a single member of a cyclic base structure create aspirocyclic structure. In yet another embodiment, the ring-formingsubstituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally form a ring of the formula -T-C(O)—(CRR′)_(q)—U—, whereinT and U are independently —NR—, —O—, —CRR′—, or a single bond, and q isan integer of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CRR′)_(s)—X′—(C″R″R″′)_(d)—, where s and d are independentlyintegers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″, and R″′ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant toinclude oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), andsilicon (Si).

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

-   (A) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,    —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,    —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, unsubstituted    alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl,    unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted    heteroaryl, and-   (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,    heteroaryl, substituted with at least one substituent selected from:-   (i) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,    —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,    —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, unsubstituted    alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl,    unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted    heteroaryl, and-   (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,    heteroaryl, substituted with at least one substituent selected from:-   (a) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,    —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,    —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, unsubstituted    alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl,    unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted    heteroaryl, and-   (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,    heteroaryl, substituted with at least one substituent selected from:    oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,    —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,    —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, unsubstituted alkyl,    unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted    heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl.

A “size-limited substituent” or “size-limited substituent group,” asused herein, means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl.

A “lower substituent” or “lower substituent group,” as used herein,means a group selected from all of the substituents described above fora “substituent group,” wherein each substituted or unsubstituted alkylis a substituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl.

In some embodiments, each substituted group described in the compoundsherein is substituted with at least one substituent group. Morespecifically, in some embodiments, each substituted alkyl, substitutedheteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl,substituted aryl, substituted heteroaryl, substituted alkylene,substituted heteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene described in the compounds herein are substituted with atleast one substituent group. In other embodiments, at least one or allof these groups are substituted with at least one size-limitedsubstituent group. In other embodiments, at least one or all of thesegroups are substituted with at least one lower substituent group.

In other embodiments of the compounds herein, each substituted orunsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀ alkyl,each substituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl. In someembodiments of the compounds herein, each substituted or unsubstitutedalkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, eachsubstituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 20 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 8 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 10 membered heteroarylene.

In some embodiments, each substituted or unsubstituted alkyl is asubstituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl. In some embodiments, each substituted orunsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene,each substituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 8 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 7 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 9 membered heteroarylene. In someembodiments, the compound is a chemical species set forth in theExamples section, figures, or tables below.

Certain compounds of the present invention possess asymmetric carbonatoms (optical or chiral centers) or double bonds; the enantiomers,racemates, diastereomers, tautomers, geometric isomers, stereoisometricforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers areencompassed within the scope of the present invention. The compounds ofthe present invention do not include those that are known in art to betoo unstable to synthesize and/or isolate. The present invention ismeant to include compounds in racemic and optically pure forms.Optically active (R)- and (S)-, or (D)- and (L)-isomers may be preparedusing chiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic bondsor other centers of geometric asymmetry, and unless specified otherwise,it is intended that the compounds include both E and Z geometricisomers.

As used herein, the term “isomers” refers to compounds having the samenumber and kind of atoms, and hence the same molecular weight, butdiffering in respect to the structural arrangement or configuration ofthe atoms.

The term “tautomer,” as used herein, refers to one of two or morestructural isomers which exist in equilibrium and which are readilyconverted from one isomeric form to another.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C— or ¹⁴C-enriched carbonare within the scope of this invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areencompassed within the scope of the present invention.

It should be noted that throughout the application that alternatives arewritten in Markush groups, for example, each amino acid position thatcontains more than one possible amino acid. It is specificallycontemplated that each member of the Markush group should be consideredseparately, thereby comprising another embodiment, and the Markush groupis not to be read as a single unit.

“Analog,” or “analogue” is used in accordance with its plain ordinarymeaning within Chemistry and Biology and refers to a chemical compoundthat is structurally similar to another compound (i.e., a so-called“reference” compound) but differs in composition, e.g., in thereplacement of one atom by an atom of a different element, or in thepresence of a particular functional group, or the replacement of onefunctional group by another functional group, or the absolutestereochemistry of one or more chiral centers of the reference compound.Accordingly, an analog is a compound that is similar or comparable infunction and appearance but not in structure or origin to a referencecompound.

The terms “a” or “an,” as used in herein means one or more. In addition,the phrase “substituted with a[n],” as used herein, means the specifiedgroup may be substituted with one or more of any or all of the namedsubstituents. For example, where a group, such as an alkyl or heteroarylgroup, is “substituted with an unsubstituted C₁-C₂₀ alkyl, orunsubstituted 2 to 20 membered heteroalkyl,” the group may contain oneor more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2to 20 membered heteroalkyls.

Moreover, where a moiety is substituted with an R substituent, the groupmay be referred to as “R-substituted.” Where a moiety is R-substituted,the moiety is substituted with at least one R substituent and each Rsubstituent is optionally different. Where a particular R group ispresent in the description of a chemical genus (such as Formula (I)), aRoman alphabetic symbol may be used to distinguish each appearance ofthat particular R group. For example, where multiple R¹³ substituentsare present, each R¹³ substituent may be distinguished as R^(13A),R^(13B), R^(13C), R^(13D), etc., wherein each of R^(13A), R^(13B),R^(13C), R^(13D), etc. is defined within the scope of the definition ofR¹³ and optionally differently.

A “detectable moiety” as used herein refers to a moiety that can becovalently or noncovalently attached to a compound or biomolecule thatcan be detected for instance, using techniques known in the art. Inembodiments, the detectable moiety is covalently attached. Thedetectable moiety may provide for imaging of the attached compound orbiomolecule. The detectable moiety may indicate the contacting betweentwo compounds. Exemplary detectable moieties are fluorophores,antibodies, reactive dies, radio-labeled moieties, magnetic contrastagents, and quantum dots. Exemplary fluorophores include fluorescein,rhodamine, GFP, coumarin, FITC, Alexa fluor, Cy3, Cy5, BODIPY, andcyanine dyes. Exemplary radionuclides include Fluorine-18, Gallium-68,and Copper-64. Exemplary magnetic contrast agents include gadolinium,iron oxide and iron platinum, and manganese.

Descriptions of compounds of the present invention are limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof sub stituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to give compounds which are notinherently unstable and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions, such asaqueous, neutral, and several known physiological conditions. Forexample, a heterocycloalkyl or heteroaryl is attached to the remainderof the molecule via a ring heteroatom in compliance with principles ofchemical bonding known to those skilled in the art thereby avoidinginherently unstable compounds.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds that are prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and thelike. Also included are salts of amino acids such as arginate and thelike, and salts of organic acids like glucuronic or galactunoric acidsand the like (see, for example, Berge et al., “Pharmaceutical Salts”,Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

Thus, the compounds of the present invention may exist as salts, such aswith pharmaceutically acceptable acids. The present invention includessuch salts. Non-limiting examples of such salts include hydrochlorides,hydrobromides, phosphates, sulfates, methanesulfonates, nitrates,maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g.,(+)-tartrates, (−)-tartrates, or mixtures thereof including racemicmixtures), succinates, benzoates, and salts with amino acids such asglutamic acid, and quaternary ammonium salts (e.g. methyl iodide, ethyliodide, and the like). These salts may be prepared by methods known tothose skilled in the art.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compound maydiffer from the various salt forms in certain physical properties, suchas solubility in polar solvents. In embodiments, compounds of thepresent invention contain both basic and acidic functionalities thatallow the compounds to be converted into either base or acid additionsalts. The neutral forms of the compounds may be regenerated bycontacting the salt with a base or acid and isolating the parentcompound in a conventional manner. The parent form of the compoundsdiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents, but, unless specifically indicated, thesalts disclosed herein are equivalent to the parent form of the compoundfor the purposes of the present invention.

In addition to salt forms, the present invention provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Prodrugs of the compounds described herein may be convertedin vivo after administration. Additionally, prodrugs can be converted tothe compounds of the present invention by chemical or biochemicalmethods in an ex vivo environment, such as, for example, when contactedwith a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of a compoundto and absorption by a subject and can be included in the compositionsof the present invention without causing a significant adversetoxicological effect on the patient. Non-limiting examples ofpharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors, salt solutions (such as Ringer's solution), alcohols, oils,gelatins, carbohydrates such as lactose, amylose or starch, fatty acidesters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, andthe like. Such preparations can be sterilized and, if desired, mixedwith auxiliary agents such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, and/or aromatic substances and the like that do notdeleteriously react with the compounds of the invention. One of skill inthe art will recognize that other pharmaceutical excipients are usefulin the present invention.

The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

A “CCR4 inhibitor” refers to a compound (e.g., compounds describedherein) that reduces the activity of CCR4 when compared to a control,such as absence of the compound or a compound with known inactivity.

The terms “polypeptide,” “peptide” and “protein” are usedinterchangeably herein to refer to a polymer of amino acid residues,wherein the polymer may optionally be conjugated to a moiety that doesnot consist of amino acids. The terms apply to amino acid polymers inwhich one or more amino acid residue is an artificial chemical mimeticof a corresponding naturally occurring amino acid, as well as tonaturally occurring amino acid polymers and non-naturally occurringamino acid polymer. In embodiments, the terms “polypeptide,” “peptide,”and “protein”, used interchangeably herein, refer to a polymeric form ofamino acids of any length, which can include genetically coded andnon-genetically coded amino acids, chemically or biochemically modifiedor derivatized amino acids, and polypeptides having modified polypeptidebackbones. The terms include fusion proteins, including, but not limitedto, fusion proteins with a heterologous amino acid sequence; fusionproteins with heterologous and homologous leader sequences, with orwithout N-terminus methionine residues; immunologically tagged proteins;and the like.

A polypeptide, or a cell is “recombinant” when it is artificial orengineered, or derived from or contains an artificial or engineeredprotein or nucleic acid (e.g. non-natural or not wild type). Forexample, a polynucleotide that is inserted into a vector or any otherheterologous location, e.g., in a genome of a recombinant organism, suchthat it is not associated with nucleotide sequences that normally flankthe polynucleotide as it is found in nature is a recombinantpolynucleotide. A protein expressed in vitro or in vivo from arecombinant polynucleotide is an example of a recombinant polypeptide.Likewise, a polynucleotide sequence that does not appear in nature, forexample a variant of a naturally occurring gene, is recombinant.

“Contacting” is used in accordance with its plain ordinary meaning andrefers to the process of allowing at least two distinct species (e.g.chemical compounds including biomolecules or cells) to becomesufficiently proximal to react, interact or physically touch. It shouldbe appreciated; however, the resulting reaction product can be produceddirectly from a reaction between the added reagents or from anintermediate from one or more of the added reagents that can be producedin the reaction mixture.

The term “contacting” may include allowing two species to react,interact, or physically touch, wherein the two species may be a compoundas described herein and a protein or enzyme. In some embodimentscontacting includes allowing a compound described herein to interactwith a protein or enzyme that is involved in a signaling pathway (e.g.,MAP kinase pathway).

As defined herein, the term “activation”, “activate”, “activating” andthe like in reference to a protein refers to conversion of a proteininto a biologically active derivative from an initial inactive ordeactivated state. The terms reference activation, or activating,sensitizing, or up-regulating signal transduction or enzymatic activityor the amount of a protein decreased in a disease.

The terms “agonist,” “activator,” “upregulator,” etc. refer to asubstance capable of detectably increasing the expression or activity ofa given gene or protein. The agonist can increase expression or activity10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to acontrol in the absence of the agonist. In certain instances, expressionor activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold orhigher than the expression or activity in the absence of the agonist. Inembodiments, an agonist is a molecule that interacts with a target tocause or promote an increase in the activation of the target. Inembodiments, activators are molecules that increase, activate,facilitate, enhance activation, sensitize, or up-regulate, e.g., a gene,protein, ligand, receptor, or cell.

As defined herein, the term “inhibition,” “inhibit,”,“inhibiting,” andthe like, in reference to a protein-inhibitor interaction meansnegatively affecting (e.g. decreasing) the activity or function of theprotein relative to the activity or function of the protein in theabsence of the inhibitor. In embodiments inhibition means negativelyaffecting (e.g. decreasing) the concentration or levels of the proteinrelative to the concentration or level of the protein in the absence ofthe inhibitor. In embodiments inhibition refers to reduction of adisease or symptoms of disease. In embodiments, inhibition refers to areduction in the activity of a particular protein target. Thus,inhibition includes, at least in part, partially or totally blockingstimulation, decreasing, preventing, or delaying activation, orinactivating, desensitizing, or down-regulating signal transduction orenzymatic activity or the amount of a protein. In embodiments,inhibition refers to a reduction of activity of a target proteinresulting from a direct interaction (e.g. an inhibitor binds to thetarget protein). In embodiments, inhibition refers to a reduction ofactivity of a target protein from an indirect interaction (e.g. aninhibitor binds to a protein that activates the target protein, therebypreventing target protein activation).

The terms “inhibitor,” “repressor” or “antagonist” or “downregulator”interchangeably refer to a substance capable of detectably decreasingthe expression or activity of a given gene or protein. The antagonistcan decrease expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 90% or more in comparison to a control in the absence of theantagonist. In certain instances, expression or activity is 1.5-fold,2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression oractivity in the absence of the antagonist. An antagonist prevents,reduces, inhibits, or neutralizes the activity of an agonist, and anantagonist can also prevent, inhibit, or reduce constitutive activity ofa target, e.g., a target receptor, even where there is no identifiedagonist. In embodiments, inhibitors are molecules that decrease, block,prevent, delay activation, inactivate, desensitize, or down-regulate,e.g., a gene, protein, ligand, receptor, or cell. An inhibitor may alsobe defined as a molecule that reduces, blocks, or inactivates aconstitutive activity. An “antagonist” is a molecule that opposes theaction(s) of an agonist.

The terms “C—C chemokine receptor type 4” and “CCR4” refer to a protein(including homologs, isoforms, and functional fragments thereof) and isa high affinity receptor for the C—C-type chemokines (e.g., CCL2(MCP-1), CCL4 (MIP-1), CCL5 (RANTES), CCL17 (TARC), and CCL22 (MDC)). Itis referred to by a number of different names in the scientificliterature, including “CC—CKR-4”, “C—C CKR-4”, “K5-5”, “CD194”,“CMKBR4”, “ChemR13”, “HGCN”, and “14099”. The term includes anyrecombinant or naturally-occurring form of CCR4 variants thereof thatmaintain CCR4 activity (e.g. within at least 30%, 40%, 50%, 60%, 70%,80%, 90%, 95%, or 100% activity compared to wildtype CCR4). The termincludes any mutant form of CCR4 variants (e.g., frameshift mutations)thereof that maintain CCR4 activity (e.g. within at least 30%, 40%, 50%,60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype CCR4). Inembodiments, the CCR4 protein encoded by the CCR4 gene has the aminoacid sequence set forth in or corresponding to Entrez 1233, UniProtP51679, or RefSeq (protein) NP_005499.1. In embodiments, the CCR4 genehas the nucleic acid sequence set forth in RefSeq (mRNA) NM_005508. Inembodiments, the amino acid sequence or nucleic acid sequence is thesequence known at the time of filing of the present application. Inembodiments, the sequence corresponds to GI:5031627. In embodiments, thesequence corresponds to NP_005499.1. In embodiments, the sequencecorresponds to NM_005508.4. In embodiments, the sequence corresponds toGI:48762930. In embodiments, the CCR4 is a human CCR4, such as a humancancer causing CCR4. Though frequently found on dendritic cells,macrophages, NK cells, platelets, and basophils, CCR4 is predominantlyassociated with T cells. It plays a role in the progression of multipleinflammation-related disorders, and, as described herein, has also beenimplicated in a number of other conditions. The genomic sequence of CCR4is present on chromosome 3 (NC_000003.12), and the CCR4 gene isconserved in a number of species, including chimpanzee, Rhesus monkey,dog, cow, mouse, rat, chicken, and zebrafish. The CCR4 polypeptidecomprises 360 amino acid residues (NP_005499.1), and, like otherchemokine receptors, CCR4 is a G protein-coupled receptor found on thesurface of leukocytes (see Horuk (1994) Trends Pharm. Sci. 15:159-165).

The term “expression” includes any step involved in the production ofthe polypeptide including, but not limited to, transcription,post-transcriptional modification, translation, post-translationalmodification, and secretion. Expression can be detected usingconventional techniques for detecting protein (e.g., ELISA, Westernblotting, flow cytometry, immunofluorescence, immunohistochemistry,etc.).

The terms “disease” or “condition” refer to a state of being or healthstatus of a patient or subject capable of being treated with thecompounds or methods provided herein. The disease may be a cancer. Thedisease may be an autoimmune disease. The disease may be an inflammatorydisease. The disease may be an infectious disease. In some furtherinstances, “cancer” refers to human cancers and carcinomas, sarcomas,adenocarcinomas, lymphomas, leukemias, etc., including solid andlymphoid cancers, kidney, breast, lung, bladder, colon, ovarian,prostate, pancreas, stomach, brain, head and neck, skin, uterine,testicular, glioma, esophagus, and liver cancer, includinghepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma,non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Celllymphomas), Hodgkin's lymphoma, leukemia (including MDS, AML, ALL, ATLLand CML), or multiple myeloma.

As used herein, the term “inflammatory disease” refers to a disease orcondition characterized by aberrant inflammation (e.g. an increasedlevel of inflammation compared to a control such as a healthy person notsuffering from a disease). Examples of inflammatory diseases includeautoimmune diseases, arthritis, rheumatoid arthritis, psoriaticarthritis, juvenile idiopathic arthritis, multiple sclerosis, systemiclupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes,diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto'sencephalitis, Hashimoto's thyroiditis, ankylosing spondylitis,psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis,auto-immune thyroiditis, Behcet's disease, Crohn's disease, ulcerativecolitis, bullous pemphigoid, sarcoidosis, ichthyosis, Gravesophthalmopathy, inflammatory bowel disease, Addison's disease, Vitiligoasthma, allergic asthma, acne vulgaris, celiac disease, chronicprostatitis, inflammatory bowel disease, pelvic inflammatory disease,reperfusion injury, ischemia reperfusion injury, stroke, sarcoidosis,transplant rejection, interstitial cystitis, atherosclerosis,scleroderma, and atopic dermatitis. Such conditions are frequentlyinextricably intertwined with other diseases, disorders and conditions.A non-limiting list of inflammatory-related diseases, disorders andconditions which may, for example, be caused by inflammatory cytokines,include, arthritis, kidney failure, lupus, asthma, psoriasis, colitis,pancreatitis, allergies, fibrosis, surgical complications (e.g., whereinflammatory cytokines prevent healing), anemia, and fibromyalgia. Otherdiseases and disorders which may be associated with chronic inflammationinclude Alzheimer's disease, congestive heart failure, stroke, aorticvalve stenosis, arteriosclerosis, osteoporosis, Parkinson's disease,infections, inflammatory bowel disease (IBD), allergic contactdermatitis and other eczemas, systemic sclerosis, transplantation andmultiple sclerosis. Some of the aforementioned diseases, disorders andconditions for which a compound (e.g., CCR4 inhibitor) of the presentinvention may be particularly efficacious (due to, for example,limitations of current therapies) are described in more detailhereafter.

As used herein, the term “cancer” refers to all types of cancer,neoplasm or malignant tumors found in mammals (e.g. humans), includingleukemia, carcinomas and sarcomas. Exemplary cancers that may be treatedwith a compound or method provided herein include brain cancer, glioma,glioblastoma, neuroblastoma, prostate cancer, colorectal cancer,pancreatic cancer, cervical cancer, gastric cancer, ovarian cancer, lungcancer, and cancer of the head. Exemplary cancers that may be treatedwith a compound or method provided herein include cancer of the thyroid,endocrine system, brain, breast, cervix, colon, head & neck, liver,kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary,sarcoma, stomach, uterus, Medulloblastoma, colorectal cancer, pancreaticcancer. Additional examples include, thyroid carcinoma,cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma,colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma,esophageal carcinoma, head and neck squamous cell carcinoma, breastinvasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma,Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma,neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer,rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia,primary brain tumors, cancer, malignant pancreatic insulanoma, malignantcarcinoid, urinary bladder cancer, premalignant skin lesions, testicularcancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer,genitourinary tract cancer, malignant hypercalcemia, endometrial cancer,adrenal cortical cancer, neoplasms of the endocrine or exocrinepancreas, medullary thyroid cancer, medullary thyroid carcinoma,melanoma, colorectal cancer, papillary thyroid cancer, hepatocellularcarcinoma, or prostate cancer.

The term “leukemia” refers broadly to progressive, malignant diseases ofthe blood-forming organs and is generally characterized by a distortedproliferation and development of leukocytes and their precursors in theblood and bone marrow. Leukemia is generally clinically classified onthe basis of (1) the duration and character of the disease-acute orchronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid(lymphogenous), or monocytic; and (3) the increase or non-increase inthe number abnormal cells in the blood-leukemic or aleukemic(subleukemic). Exemplary leukemias that may be treated with a compoundor method provided herein include, for example, acute nonlymphocyticleukemia, chronic lymphocytic leukemia, acute granulocytic leukemia,chronic granulocytic leukemia, acute promyelocytic leukemia, adultT-cell leukemia, aleukemic leukemia, a leukocythemic leukemia,basophylic leukemia, blast cell leukemia, bovine leukemia, chronicmyelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilicleukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia,hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia,acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia,lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia,lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia,megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia,myeloblastic leukemia, myelocytic leukemia, myeloid granulocyticleukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cellleukemia, multiple myeloma, plasmacytic leukemia, promyelocyticleukemia, Rieder cell leukemia, Schilling's leukemia, stem cellleukemia, subleukemic leukemia, or undifferentiated cell leukemia.

The term “sarcoma” generally refers to a tumor which is made up of asubstance like the embryonic connective tissue and is generally composedof closely packed cells embedded in a fibrillar or homogeneoussubstance. Sarcomas that may be treated with a compound or methodprovided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma,melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adiposesarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma,botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma,Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing'ssarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma,granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmentedhemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma,immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma,Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymomasarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma,serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

The term “melanoma” is taken to mean a tumor arising from themelanocytic system of the skin and other organs. Melanomas that may betreated with a compound or method provided herein include, for example,acral-lentiginous melanoma, amelanotic melanoma, benign juvenilemelanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma,juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodularmelanoma, subungal melanoma, or superficial spreading melanoma.

The term “carcinoma” refers to a malignant new growth made up ofepithelial cells tending to infiltrate the surrounding tissues and giverise to metastases. Exemplary carcinomas that may be treated with acompound or method provided herein include, for example, thyroidcarcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneousmelanoma, colon adenocarcinoma, rectum adenocarcinoma, stomachadenocarcinoma, esophageal carcinoma, head and neck squamous cellcarcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamouscell carcinoma, medullary thyroid carcinoma, familial medullary thyroidcarcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma,adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenalcortex, alveolar carcinoma, alveolar cell carcinoma, basal cellcarcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamouscell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma,bronchogenic carcinoma, cerebriform carcinoma, cholangiocellularcarcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma,corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinomacutaneum, cylindrical carcinoma, cylindrical cell carcinoma, ductcarcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma,epiermoid carcinoma, carcinoma epitheliale adenoides, exophyticcarcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatinifornicarcinoma, gelatinous carcinoma, giant cell carcinoma, carcinomagigantocellulare, glandular carcinoma, granulosa cell carcinoma,hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma,Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma,infantile embryonal carcinoma, carcinoma in situ, intraepidermalcarcinoma, intraepithelial carcinoma, Krompecher's carcinoma,Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma,carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma,carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinomamolle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare,mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinomamyxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinomaossificans, osteoid carcinoma, papillary carcinoma, periportalcarcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceouscarcinoma, renal cell carcinoma of kidney, reserve cell carcinoma,carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma,carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex,small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma,spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma,squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum,carcinoma telangiectodes, transitional cell carcinoma, carcinomatuberosum, tuberous carcinoma, verrucous carcinoma, or carcinomavillosum.

As used herein, the term “autoimmune disease” refers to a disease orcondition in which a subject's immune system has an aberrant immuneresponse against a substance that does not normally elicit an immuneresponse in a healthy subject. Examples of autoimmune diseases that maybe treated with a compound, pharmaceutical composition, or methoddescribed herein include Acute Disseminated Encephalomyelitis (ADEM),Acute necrotizing hemorrhagic leukoencephalitis, Addison's disease,Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosingspondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome(APS), Autoimmune angioedema, Autoimmune aplastic anemia, Autoimmunedysautonomia, Autoimmune hepatitis, Autoimmune hyperlipidemia,Autoimmune immunodeficiency, Autoimmune inner ear disease (AIED),Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune pancreatitis,Autoimmune retinopathy, Autoimmune thrombocytopenic purpura (ATP),Autoimmune thyroid disease, Autoimmune urticaria, Axonal or neuronalneuropathies, Balo disease, Behcet's disease, Bullous pemphigoid,Cardiomyopathy, Castleman disease, Celiac disease, Chagas disease,Chronic fatigue syndrome, Chronic inflammatory demyelinatingpolyneuropathy (CIDP), Chronic recurrent multifocal ostomyelitis (CRMO),Churg-Strauss syndrome, Cicatricial pemphigoid/benign mucosalpemphigoid, Crohn's disease, Cogans syndrome, Cold agglutinin disease,Congenital heart block, Coxsackie myocarditis, CREST disease, Essentialmixed cryoglobulinemia, Demyelinating neuropathies, Dermatitisherpetiformis, Dermatomyositis, Devic's disease (neuromyelitis optica),Discoid lupus, Dressler's syndrome, Endometriosis, Eosinophilicesophagitis, Eosinophilic fasciitis, Erythema nodosum, Experimentalallergic encephalomyelitis, Evans syndrome, Fibromyalgia, Fibrosingalveolitis, Giant cell arteritis (temporal arteritis), Giant cellmyocarditis, Glomerulonephritis, Goodpasture's syndrome, Granulomatosiswith Polyangiitis (GPA) (formerly called Wegener's Granulomatosis),Graves' disease, Guillain-Barre syndrome, Hashimoto's encephalitis,Hashimoto's thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura,Herpes gestationis, Hypogammaglobulinemia, Idiopathic thrombocytopenicpurpura (ITP), IgA nephropathy, IgG4-related sclerosing disease,Immunoregulatory lipoproteins, Inclusion body myositis, Interstitialcystitis, Juvenile arthritis, Juvenile diabetes (Type 1 diabetes),Juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome,Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneousconjunctivitis, Linear IgA disease (LAD), Lupus (SLE), Lyme disease,chronic, Meniere's disease, Microscopic polyangiitis, Mixed connectivetissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multiplesclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica(Devic's), Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis,Palindromic rheumatism, PANDAS (Pediatric Autoimmune NeuropsychiatricDisorders Associated with Streptococcus), Paraneoplastic cerebellardegeneration, Paroxysmal nocturnal hemoglobinuria (PNH), Parry Rombergsyndrome, Parsonnage-Turner syndrome, Pars planitis (peripheraluveitis), Pemphigus, Peripheral neuropathy, Perivenousencephalomyelitis, Pernicious anemia, POEMS syndrome, Polyarteritisnodosa, Type I, II, & III autoimmune polyglandular syndromes,Polymyalgia rheumatica, Polymyositis, Postmyocardial infarctionsyndrome, Postpericardiotomy syndrome, Progesterone dermatitis, Primarybiliary cirrhosis, Primary sclerosing cholangitis, Psoriasis, Psoriaticarthritis, Idiopathic pulmonary fibrosis, Pyoderma gangrenosum, Pure redcell aplasia, Raynauds phenomenon, Reactive Arthritis, Reflexsympathetic dystrophy, Reiter's syndrome, Relapsing polychondritis,Restless legs syndrome, Retroperitoneal fibrosis, Rheumatic fever,Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis,Scleroderma, Sjogren's syndrome, Sperm & testicular autoimmunity, Stiffperson syndrome, Subacute bacterial endocarditis (SBE), Susac'ssyndrome, Sympathetic ophthalmia, Takayasu's arteritis, Temporalarteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP),Tolosa-Hunt syndrome, Transverse myelitis, Type 1 diabetes, Ulcerativecolitis, Undifferentiated connective tissue disease (UCTD), Uveitis,Vasculitis, Vesiculobullous dermatosis, Vitiligo, or Wegener'sgranulomatosis (i.e., Granulomatosis with Polyangiitis (GPA).

As used herein, the term “inflammatory disease” refers to a disease orcondition characterized by aberrant inflammation (e.g. an increasedlevel of inflammation compared to a control such as a healthy person notsuffering from a disease). Examples of inflammatory diseases includetraumatic brain injury, arthritis, rheumatoid arthritis, psoriaticarthritis, juvenile idiopathic arthritis, multiple sclerosis, systemiclupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes,diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto'sencephalitis, Hashimoto's thyroiditis, ankylosing spondylitis,psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis,auto-immune thyroiditis, Behcet's disease, Crohn's disease, ulcerativecolitis, bullous pemphigoid, sarcoidosis, ichthyosis, Gravesophthalmopathy, inflammatory bowel disease, Addison's disease, Vitiligo,asthma, asthma, allergic asthma, acne vulgaris, celiac disease, chronicprostatitis, inflammatory bowel disease, pelvic inflammatory disease,reperfusion injury, sarcoidosis, transplant rejection, interstitialcystitis, atherosclerosis, and atopic dermatitis.

The terms “treating”, or “treatment” refer to any indicia of success inthe therapy or amelioration of an injury, disease, pathology orcondition, including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the injury,pathology or condition more tolerable to the patient; slowing in therate of degeneration or decline; making the final point of degenerationless debilitating; improving a patient's physical or mental well-being.The treatment or amelioration of symptoms can be based on objective orsubjective parameters; including the results of a physical examination,neuropsychiatric exams, and/or a psychiatric evaluation. The term“treating” and conjugations thereof, may include prevention of aninjury, pathology, condition, or disease. In embodiments, treating ispreventing. In embodiments, treating does not include preventing.

“Treating” or “treatment” as used herein (and as well-understood in theart) also broadly includes any approach for obtaining beneficial ordesired results in a subject's condition, including clinical results.Beneficial or desired clinical results can include, but are not limitedto, alleviation or amelioration of one or more symptoms or conditions,diminishment of the extent of a disease, stabilizing (i.e., notworsening) the state of disease, prevention of a disease's transmissionor spread, delay or slowing of disease progression, amelioration orpalliation of the disease state, diminishment of the reoccurrence ofdisease, and remission, whether partial or total and whether detectableor undetectable. In other words, “treatment” as used herein includes anycure, amelioration, or prevention of a disease. Treatment may preventthe disease from occurring; inhibit the disease's spread; relieve thedisease's symptoms (e.g., ocular pain, seeing halos around lights, redeye, very high intraocular pressure), fully or partially remove thedisease's underlying cause, shorten a disease's duration, or do acombination of these things.

“Treating” and “treatment” as used herein include prophylactictreatment. Treatment methods include administering to a subject atherapeutically effective amount of a compound described herein. Theadministering step may consist of a single administration or may includea series of administrations. The length of the treatment period dependson a variety of factors, such as the severity of the condition, the ageof the patient, the concentration of the compound, the activity of thecompositions used in the treatment, or a combination thereof. It willalso be appreciated that the effective dosage of an agent used for thetreatment or prophylaxis may increase or decrease over the course of aparticular treatment or prophylaxis regime. Changes in dosage may resultand become apparent by standard diagnostic assays known in the art. Insome instances, chronic administration may be required. For example, thecompositions are administered to the subject in an amount and for aduration sufficient to treat the patient.

The term “prevent” refers to a decrease in the occurrence of diseasesymptoms in a patient. As indicated above, the prevention may becomplete (no detectable symptoms) or partial, such that fewer symptomsare observed than would likely occur absent treatment. In embodiments,prevent refers to slowing the progression of the disease, disorder orcondition or inhibiting progression thereof to a harmful or otherwiseundesired state.

“Patient” or “subject in need thereof” refers to a living organismsuffering from or prone to a disease or condition that can be treated byadministration of a pharmaceutical composition as provided herein.Non-limiting examples include humans, other mammals, bovines, rats,mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammaliananimals. In some embodiments, a patient is human.

An “effective amount” is an amount sufficient for a compound toaccomplish a stated purpose relative to the absence of the compound(e.g. achieve the effect for which it is administered, treat a disease,reduce enzyme activity, increase enzyme activity, reduce a signalingpathway, or reduce one or more symptoms of a disease or condition). Anexample of an “effective amount” is an amount sufficient to contributeto the treatment, prevention, or reduction of a symptom or symptoms of adisease, which could also be referred to as a “therapeutically effectiveamount.” A “reduction” of a symptom or symptoms (and grammaticalequivalents of this phrase) means decreasing of the severity orfrequency of the symptom(s), or elimination of the symptom(s). A“prophylactically effective amount” of a drug is an amount of a drugthat, when administered to a subject, will have the intendedprophylactic effect, e.g., preventing or delaying the onset (orreoccurrence) of an injury, disease, pathology or condition, or reducingthe likelihood of the onset (or reoccurrence) of an injury, disease,pathology, or condition, or their symptoms. The full prophylactic effectdoes not necessarily occur by administration of one dose, and may occuronly after administration of a series of doses. Thus, a prophylacticallyeffective amount may be administered in one or more administrations. An“activity decreasing amount,” as used herein, refers to an amount ofantagonist required to decrease the activity of an enzyme relative tothe absence of the antagonist. A “function disrupting amount,” as usedherein, refers to the amount of antagonist required to disrupt thefunction of an enzyme or protein relative to the absence of theantagonist. The exact amounts will depend on the purpose of thetreatment, and will be ascertainable by one skilled in the art usingknown techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms(vols. 1-3, 1992); Lloyd, The Art, Science and Technology ofPharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999);and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003,Gennaro, Ed., Lippincott, Williams & Wilkins). The therapeuticallyeffective amount can be ascertained by measuring relevant physiologicaleffects, and it can be adjusted in connection with the dosing regimenand diagnostic analysis of the subject's condition, and the like. By wayof example, measurement of the serum level of a CCR4 inhibitor (or,e.g., a metabolite thereof) at a particular time post-administration maybe indicative of whether a therapeutically effective amount has beenadministered.

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Targetconcentrations will be those concentrations of active compound(s) thatare capable of achieving the methods described herein, as measured usingthe methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for usein humans can also be determined from animal models. For example, a dosefor humans can be formulated to achieve a concentration that has beenfound to be effective in animals. The dosage in humans can be adjustedby monitoring compounds effectiveness and adjusting the dosage upwardsor downwards, as described above. Adjusting the dose to achieve maximalefficacy in humans based on the methods described above and othermethods is well within the capabilities of the ordinarily skilledartisan. Adjusting the dose to achieve maximal therapeutic windowefficacy or toxicity in humans based on the methods described above andother methods is well within the capabilities of the ordinarily skilledartisan.

The term “therapeutically effective amount,” as used herein, refers tothat amount of the therapeutic agent sufficient to ameliorate thedisorder, as described above. For example, for the given parameter, atherapeutically effective amount will show an increase or decrease of atleast 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least100%. Therapeutic efficacy can also be expressed as “-fold” increase ordecrease. For example, a therapeutically effective amount can have atleast a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over acontrol.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present invention should be sufficient to effect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side-effects. Determination of the proper dosage for aparticular situation is within the skill of the practitioner. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached. Dosage amounts and intervals can be adjusted individually toprovide levels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

As used herein, the term “administering” means oral administration,administration as a suppository, topical contact, intravenous,parenteral, intraperitoneal, intramuscular, intralesional, intrathecal,intracranial, intranasal or subcutaneous administration, or theimplantation of a slow-release device, e.g., a mini-osmotic pump, to asubject. Administration is by any route, including parenteral andtransmucosal (e.g., buccal, sublingual, palatal, gingival, nasal,vaginal, rectal, or transdermal). Parenteral administration includes,e.g., intravenous, intramuscular, intra-arteriole, intradermal,subcutaneous, intraperitoneal, intraventricular, and intracranial. Othermodes of delivery include, but are not limited to, the use of liposomalformulations, intravenous infusion, transdermal patches, etc. By“co-administer” it is meant that a composition described herein isadministered at the same time, just prior to, or just after theadministration of one or more additional therapies (e.g. anti-canceragent, chemotherapeutic, or treatment for a neurodegenerative disease).The compound of the invention can be administered alone or can becoadministered to the patient. Coadministration is meant to includesimultaneous or sequential administration of the compound individuallyor in combination (more than one compound or agent). Thus, thepreparations can also be combined, when desired, with other activesubstances (e.g. to reduce metabolic degradation). The compositions ofthe present invention can be delivered by transdermally, by a topicalroute, formulated as applicator sticks, solutions, suspensions,emulsions, gels, creams, ointments, pastes, jellies, paints, powders,and aerosols. Oral preparations include tablets, pills, powder, dragees,capsules, liquids, lozenges, cachets, gels, syrups, slurries,suspensions, etc., suitable for ingestion by the patient. Solid formpreparations include powders, tablets, pills, capsules, cachets,suppositories, and dispersible granules. Liquid form preparationsinclude solutions, suspensions, and emulsions, for example, water orwater/propylene glycol solutions. The compositions of the presentinvention may additionally include components to provide sustainedrelease and/or comfort. Such components include high molecular weight,anionic mucomimetic polymers, gelling polysaccharides and finely-divideddrug carrier substrates. These components are discussed in greaterdetail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760.The entire contents of these patents are incorporated herein byreference in their entirety for all purposes. The compositions of thepresent invention can also be delivered as microspheres for slow releasein the body. For example, microspheres can be administered viaintradermal injection of drug-containing microspheres, which slowlyrelease subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645,1995; as biodegradable and injectable gel formulations (see, e.g., GaoPharm. Res. 12:857-863, 1995); or, as microspheres for oraladministration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674,1997). In another embodiment, the formulations of the compositions ofthe present invention can be delivered by the use of liposomes whichfuse with the cellular membrane or are endocytosed, i.e., by employingreceptor ligands attached to the liposome, that bind to surface membraneprotein receptors of the cell resulting in endocytosis. By usingliposomes, particularly where the liposome surface carries receptorligands specific for target cells, or are otherwise preferentiallydirected to a specific organ, one can focus the delivery of thecompositions of the present invention into the target cells in vivo.(See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn,Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm.46:1576-1587, 1989). The compositions of the present invention can alsobe delivered as nanoparticles.

By “co-administer” it is meant that a composition described herein isadministered at the same time, just prior to, or just after theadministration of one or more additional therapies. The compounds of theinvention can be administered alone or can be coadministered to thepatient. Coadministration is meant to include simultaneous or sequentialadministration of the compounds individually or in combination (morethan one compound). The compositions of the present invention can bedelivered transdermally, by a topical route, or formulated as applicatorsticks, solutions, suspensions, emulsions, gels, creams, ointments,pastes, jellies, paints, powders, and aerosols.

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Targetconcentrations will be those concentrations of active compound(s) thatare capable of achieving the methods described herein, as measured usingthe methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for usein humans can also be determined from animal models. For example, a dosefor humans can be formulated to achieve a concentration that has beenfound to be effective in animals. The dosage in humans can be adjustedby monitoring compounds effectiveness and adjusting the dosage upwardsor downwards, as described above. Adjusting the dose to achieve maximalefficacy in humans based on the methods described above and othermethods is well within the capabilities of the ordinarily skilledartisan.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present invention should be sufficient to affect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side-effects. Determination of the proper dosage for aparticular situation is within the skill of the practitioner. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached.

Dosage amounts and intervals can be adjusted individually to providelevels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

Utilizing the teachings provided herein, an effective prophylactic ortherapeutic treatment regimen can be planned that does not causesubstantial toxicity and yet is effective to treat the clinical symptomsdemonstrated by the particular patient. This planning should involve thecareful choice of active compound by considering factors such ascompound potency, relative bioavailability, patient body weight,presence and severity of adverse side effects, preferred mode ofadministration and the toxicity profile of the selected agent.

The compounds described herein can be used in combination with oneanother, with other active agents known to be useful in treating cancer(e.g. colon cancer), cardiovascular disease, metabolic disease, immuneor inflammatory disease or disorder.

In some embodiments, co-administration includes administering one activeagent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 2 days, 4days, 1 week or 1 month of a second active agent. Co-administrationincludes administering two active agents simultaneously, approximatelysimultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes ofeach other), or sequentially in any order. In some embodiments,co-administration can be accomplished by co-formulation, i.e., preparinga single pharmaceutical composition including both active agents. Inother embodiments, the active agents can be formulated separately. Inanother embodiment, the active and/or adjunctive agents may be linked orconjugated to one another. In some embodiments, the compounds describedherein may be combined with treatments for cancer (e.g. colon cancer),cardiovascular disease, metabolic disease, immune or inflammatorydisease or disorder.

“Cardiovascular agent” is used in accordance with its plain ordinarymeaning and refers to a composition (e.g. compound, drug, antagonist,inhibitor, modulator) used in any way to treat conditions of the heart,or the circulatory or vascular system. In some embodiments, acardiovascular agent is an agent identified herein having utility inmethods of treating cardiovascular disease or disorder. In someembodiments, a cardiovascular agent is an agent approved by the FDA orsimilar regulatory agency of a country other than the USA, for treatingcardiovascular disease or disorder.

“Anti-inflammatory agent” is used in accordance with its plain ordinarymeaning and refers to a composition (e.g. compound, drug, antagonist,inhibitor, modulator) used in any way to reduce inflammation orswelling. In some embodiments, an anti-inflammatory agent is an agentidentified herein having utility in methods of treating an inflammatorydisease or disorder. In some embodiments, an anti-inflammatory agent isan agent approved by the FDA or similar regulatory agency of a countryother than the USA, for reducing swelling and inflammation.

The compounds described herein can be administered to treat an immune orinflammatory disease or disorder, a cardiovascular or metabolic diseaseor disorder and/or cancer. In this regard, the compounds disclosedherein may be administered either alone to treat such diseases ordisorders or may be co-administered with another therapeutic agent totreat such diseases or disorders.

The compounds disclosed herein may be co-administered with a cytokine oragonist or antagonist of cytokine function, (including agents which acton cytokine signaling pathways such as modulators of the SOCS system)including alpha-, beta-, and gamma-interferons; insulin-like growthfactor type I (IGF-1); interleukins (IL) including IL1 to 17, andinterleukin antagonists or inhibitors such as analcinra; tumour necrosisfactor alpha (TNF-.alpha.) inhibitors such as anti-TNF monoclonalantibodies (for example infliximab; adalimumab, and CDP-870) and TNFreceptor antagonists including immunoglobulin molecules (such asetanercept) and low-molecular-weight agents such as pentoxyfylline.

The compounds disclosed herein may be co-administered with ananti-inflammatory agent, such as thalidomide or a derivative thereof, aretinoid, dithranol or calcipotriol, a non-steroidal anti-inflammatoryagent (hereinafter NSAID) including non-selective cyclo-oxygenaseCOX-1/COX-2 inhibitors whether applied topically or systemically (suchas piroxicam, diclofenac, propionic acids such as naproxen,flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such asmefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones suchas phenylbutazone, salicylates such as aspirin); selective COX-2inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib,lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibitingnitric oxide donors (CINODs); glucocorticosteroids (whether administeredby topical, oral, intramuscular, intravenous, or intra-articularroutes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine;auranofin or other parenteral or oral gold preparations; analgesics;diacerein; intra-articular therapies such as hyaluronic acidderivatives; and nutritional supplements such as glucosamine.

The compounds disclosed herein may be co-administered with a calciumchannel blocker, a beta-adrenoceptor blocker, an angiotensin-convertingenzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipidlowering agent such as a statin or a fibrate; a modulator of blood cellmorphology such as pentoxyfylline; thrombolytic, or an anticoagulantsuch as a platelet aggregation inhibitor.

“Anti-cancer agent” is used in accordance with its plain ordinarymeaning and refers to a composition (e.g. compound, drug, antagonist,inhibitor, modulator) having antineoplastic properties or the ability toinhibit the growth or proliferation of cells. In some embodiments, ananti-cancer agent is a chemotherapeutic. In some embodiments, ananti-cancer agent is an agent identified herein having utility inmethods of treating cancer. In some embodiments, an anti-cancer agent isan agent approved by the FDA or similar regulatory agency of a countryother than the USA, for treating cancer. Examples of anti-cancer agentsinclude, but are not limited to, MEK (e.g. MEK1, MEK2, or MEK1 and MEK2)inhibitors (e.g. XL518, CI-1040, PD035901, selumetinib/AZD6244,GSK1120212/trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901,U0126, PD98059, TAK-733, PD318088, AS703026, BAY 869766), alkylatingagents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan,melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogenmustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil,meiphalan), ethylenimine and methylmelamines (e.g., hexamethlymelamine,thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g.,carmustine, lomusitne, semustine, streptozocin), triazenes(decarbazine)), anti-metabolites (e.g., 5-azathioprine, leucovorin,capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folicacid analog (e.g., methotrexate), or pyrimidine analogs (e.g.,fluorouracil, floxouridine, Cytarabine), purine analogs (e.g.,mercaptopurine, thioguanine, pentostatin), etc.), plant alkaloids (e.g.,vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin,paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g.,irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate,teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin,daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin,mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g.cisplatin, oxaloplatin, carboplatin), anthracenedione (e.g.,mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazinederivative (e.g., procarbazine), adrenocortical suppressant (e.g.,mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide),antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g.,L-asparaginase), inhibitors of mitogen-activated protein kinasesignaling (e.g. U0126, PD98059, PD184352, PD0325901, ARRY-142886,SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002, Sykinhibitors, mTOR inhibitors, antibodies (e.g., rituxan), gossyphol,genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA),bryostatin, tumor necrosis factor-related apoptosis-inducing ligand(TRAIL), 5-aza-2′-deoxycytidine, all trans retinoic acid, doxorubicin,vincristine, etoposide, gemcitabine, imatinib (Gleevec®), geldanamycin,17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol,LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, PD184352,20-epi-1, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen,prostatic carcinoma; antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2;capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRestM3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinaseinhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin B;combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; didox; diethylnorspermine;dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol;dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA;ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene;emitefur; epirubicin; epristeride; estramustine analogue; estrogenagonists; estrogen antagonists; etanidazole; etoposide phosphate;exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin;pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RH retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen-binding protein; sizofuran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatinstimalamer, Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin,acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin;aldesleukin; altretamine; ambomycin; ametantrone acetate;aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase;asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa;bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin;bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol;chlorambucil; cirolemycin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride;decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate;diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene;droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate;eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate;epipropidine; epirubicin hydrochloride; erbulozole; esorubicinhydrochloride; estramustine; estramustine phosphate sodium; etanidazole;etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;fazarabine; fenretinide; floxuridine; fludarabine phosphate;fluorouracil; fluorocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; iimofosine; interleukin I1 (includingrecombinant interleukin II, or r1L.sub.2), interferon alfa-2a;interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferonbeta-1a; interferon gamma-1b; iproplatin; irinotecan hydrochloride;lanreotide acetate; letrozole; leuprolide acetate; liarozolehydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride;masoprocol; maytansine; mechlorethamine hydrochloride; megestrolacetate; melengestrol acetate; melphalan; menogaril; mercaptopurine;methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide;mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper;mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazoie;nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin;pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan;piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium;porfiromycin; prednimustine; procarbazine hydrochloride; puromycin;puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol;safingol hydrochloride; semustine; simtrazene; sparfosate sodium;sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin;streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium;tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicinhydrochloride, agents that arrest cells in the G2-M phases and/ormodulate the formation or stability of microtubules, (e.g. Taxol™ (i.e.paclitaxel), Taxotere™, compounds comprising the taxane skeleton,Erbulozole (i.e. R-55104), Dolastatin 10 (i.e. DLS-10 and NSC-376128),Mivobulin isethionate (i.e. as CI-980), Vincristine, NSC-639829,Discodermolide (i.e. as NVP-XX-A-296), ABT-751 (Abbott, i.e. E-7010),Altorhyrtins (e.g. Altorhyrtin A and Altorhyrtin C), Spongistatins (e.g.Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4,Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, andSpongistatin 9), Cemadotin hydrochloride (i.e. LU-103793 andNSC-D-669356), Epothilones (e.g. Epothilone A, Epothilone B, EpothiloneC (i.e. desoxyepothilone A or dEpoA), Epothilone D (i.e. KOS-862, dEpoB,and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone BN-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B(i.e. BMS-310705), 21-hydroxyepothilone D (i.e. Desoxyepothilone F anddEpoF), 26-fluoroepothilone, Auristatin PE (i.e. NSC-654663), Soblidotin(i.e. TZT-1027), LS-4559-P (Pharmacia, i.e. LS-4577), LS-4578(Pharmacia, i.e. LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia),RPR-112378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877(Fujisawa, i.e. WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2(Hungarian Academy of Sciences), BSF-223651 (BASF, i.e. ILX-651 andLU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis),AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko),IDN-5005 (Indena), Cryptophycin 52 (i.e. LY-355703), AC-7739 (Ajinomoto,i.e. AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, i.e. AVE-8062,AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide, TubulysinA, Canadensol, Centaureidin (i.e. NSC-106969), T-138067 (Tularik, i.e.T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute, i.e.DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas StateUniversity), Oncocidin A1 (i.e. BTO-956 and DIME), DDE-313 (ParkerHughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker HughesInstitute), SPA-1 (Parker Hughes Institute, i.e. SPIKET-P), 3-IAABU(Cytoskeleton/Mt. Sinai School of Medicine, i.e. MF-569), Narcosine(also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972(Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School ofMedicine, i.e. MF-191), TMPN (Arizona State University), Vanadoceneacetylacetonate, T-138026 (Tularik), Monsatrol, lnanocine (i.e.NSC-698666), 3-IAABE (Cytoskeleton/Mt. Sinai School of Medicine),A-204197 (Abbott), T-607 (Tuiarik, i.e. T-900607), RPR-115781 (Aventis),Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin,lsoeleutherobin A, and Z-Eleutherobin), Caribaeoside, Caribaeolin,Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica),Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A,TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (−)-Phenylahistin(i.e. NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica),Myoseverin B, D-43411 (Zentaris, i.e. D-81862), A-289099 (Abbott),A-318315 (Abbott), HTI-286 (i.e. SPA-110, trifluoroacetate salt)(Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI),Resverastatin phosphate sodium, BPR-OY-007 (National Health ResearchInstitutes), and SSR-250411 (Sanofi)), steroids (e.g., dexamethasone),finasteride, aromatase inhibitors, gonadotropin-releasing hormoneagonists (GnRH) such as goserelin or leuprolide, adrenocorticosteroids(e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate,megestrol acetate, medroxyprogesterone acetate), estrogens (e.g.,diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen),androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen(e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guérin(BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonalantibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, andanti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonalantibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy(e.g., anti-CD20 monoclonal antibody conjugated to ¹¹¹In, ⁹⁰Y, or ¹³¹I,etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin,epirubicin, topotecan, itraconazole, vindesine, cerivastatin,vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan,clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib,gefitinib, EGFR inhibitors, epidermal growth factor receptor(EGFR)-targeted therapy or therapeutic (e.g. gefitinib (Iressa™),erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™),panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib/BIBW2992,CI-1033/canertinib, neratinib/HKI-272, CP-724714, TAK-285, AST-1306,ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804, OSI-420/desmethylerlotinib, AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002,WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib,sunitinib, dasatinib, or the like.

“Chemotherapeutic” or “chemotherapeutic agent” is used in accordancewith its plain ordinary meaning and refers to a chemical composition orcompound having antineoplastic properties or the ability to inhibit thegrowth or proliferation of cells.

Additionally, the compounds described herein can be co-administered withconventional immunotherapeutic agents including, but not limited to,immunostimulants (e.g., Bacillus Calmette-Guérin (BCG), levamisole,interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g.,anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonalantibodies), immunotoxins (e.g., anti-CD33 monoclonalantibody-calicheamicin conjugate, anti-CD22 monoclonalantibody-pseudomonas exotoxin conjugate, etc.), and radioimmunotherapy(e.g., anti-CD20 monoclonal antibody conjugated to ¹¹¹In, ⁹⁰Y, or ¹³¹I,etc.).

The compounds disclosed herein may be co-administered with anantiproliferative/antineoplastic drug or a combination thereof, as usedin medical oncology, such as an alkylating agent (for examplecis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan,chlorambucil, busulphan or a nitrosourea); an antimetabolite (forexample an antifolate such as a fluoropyrimidine like 5-fluorouracil ortegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea,gemcitabine or paclitaxel); an antitumour antibiotic (for example ananthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin,epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); anantimitotic agent (for example a vinca alkaloid such as vincristine,vinblastine, vindesine or vinorelbine, or a taxoid such as taxol ortaxotere); or a topoisomerase inhibitor (for example anepipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecanor a camptothecin); (ii) a cytostatic agent such as an antioestrogen(for example tamoxifen, toremifene, raloxifene, droloxifene oriodoxyfene), an oestrogen receptor down regulator (for examplefulvestrant), an antiandrogen (for example bicalutamide, flutamide,nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist(for example goserelin, leuprorelin or buserelin), a progestogen (forexample megestrol acetate), an aromatase inhibitor (for example asanastrozole, letrozole, vorazole or exemestane) or an inhibitor of5.alpha.-reductase such as finasteride; (iii) an agent which inhibitscancer cell invasion (for example a metalloproteinase inhibitor likemarimastat or an inhibitor of urokinase plasminogen activator receptorfunction); (iv) an inhibitor of growth factor function, for example: agrowth factor antibody (for example the anti-erbb2 antibody trastuzumab,or the anti-erbb1 antibody cetuximab [C225]), a farnesyl transferaseinhibitor, a tyrosine kinase inhibitor or a serine/threonine kinaseinhibitor, an inhibitor of the epidermal growth factor family (forexample an EGFR family tyrosine kinase inhibitor such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoli-n-4-amine(gefitinib, AZD 1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) or6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoli-n-4-amine(CI 1033)), an inhibitor of the platelet-derived growth factor family,or an inhibitor of the hepatocyte growth factor family; (v) anantiangiogenic agent such as one which inhibits the effects of vascularendothelial growth factor (for example the anti-vascular endothelialcell growth factor antibody bevacizumab, a compound disclosed in WO97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound thatworks by another mechanism (for example linomide, an inhibitor ofintegrin .alpha.v.beta.3 function or an angiostatin); (vi) a vasculardamaging agent such as combretastatin A4, or a compound disclosed in WO99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO02/08213; (vii) an agent used in antisense therapy, for example onedirected to one of the targets listed above, such as ISIS 2503, ananti-ras antisense; (viii) an agent used in a gene therapy approach, forexample approaches to replace aberrant genes such as aberrant p53 oraberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy)approaches such as those using cytosine deaminase, thymidine kinase or abacterial nitroreductase enzyme and approaches to increase patienttolerance to chemotherapy or radiotherapy such as multi-drug resistancegene therapy; or (ix) an agent used in an immunotherapeutic approach,for example ex-vivo and in-vivo approaches to increase theimmunogenicity of patient tumour cells, such as transfection withcytokines such as interleukin 2, interleukin 4 or granulocyte-macrophagecolony stimulating factor, approaches to decrease T-cell anergy,approaches using transfected immune cells such as cytokine-transfecteddendritic cells, approaches using cytokine-transfected tumour cell linesand approaches using anti-idiotypic antibodies.

In embodiments, the compounds disclosed herein can be co-administeredwith an antibody, such as a monoclonal antibody targeting B-Lymphocytes(such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMaxI1-15) or antibody modulating Ig function such as anti-IgE (for exampleomalizumab).

In embodiments, treatment of cancer includes administration of aneffective amount of at least two of the following: a CCR4 inhibitor, aninhibitor of the PD-L1/PD-1 pathway, an inhibitor of CTLA-4, anagonistic antibody of CD137 (4-1BB). In some embodiments, the method maycomprise the use of two or more combinations.

In embodiments, treatment of cancer includes an effective amount of atleast two or more of the following: a CCR4 inhibitor and any combinationof agent that may be an immune modulator such as, but not limited to,those listed in Table 1. These immune modulators can be depletingantibodies, neutralizing antibodies, blocking antibodies, agonisticantibodies, small molecule modulators (inhibitors or stimulators) orsmall molecule analogs.

TABLE 1 Target or Regulatory Therapy Examples of Agents Mechanism TIM-3TSR-022, MGB453 Checkpoint- receptor LAG-3 BMS-986016, IMP321Checkpoint- receptor B7-H3 MGA271, MGD-009 Checkpoint- receptor TIGITRG-6058 Checkpoint- receptor BTLA Checkpoint- receptor CD28 AMG 557,Checkpoint- receptor CD40 SEA-CD40, dacetuzumab, Checkpoint- CP-870,893,Chi Lob 7/4, receptor lucatumumab CD80 galiximab Checkpoint- receptorGITR INCAGN1876, TRX518, Checkpoint- receptor ICOS MEDI-570 Checkpoint-receptor OX40 MEDI-6469, INCAGN1949, Checkpoint- (CD134) huMab OX40L,receptor NKG2A monalizumab Checkpoint- receptor TGF-beta Galunisertib,luspatercept, Cytokines YH-14618, dalantercept, BG-00011, trabedersen,isth-0036 ace-083, IL2 NKTR-214, recombinant Cytokines IL2, aldesleukinIL12 EGEN-001, NHS-IL12 Cytokines IL7 Recombinant IL-7, Cytokines IL15NIZ-985, ALT-803, Cytokines IL21 Recombinant IL-21, anti- CytokinesCD20.IL21, IL13 Tralokinumab, dupilumab CSF1R cabiralizumab CytokinePI3K delta INCB50465, idealisib, Kinase TGR-1202, AMG319, PI3K gammaIPI-549 Kinase DNMT (DNA Azacytidine, decitabine, Epigenetic methylguadecitabine, Regulator transferase inhibitor) HDAC Vorinostat,Panobinostat, Epigenetic (histone belinostat, entinostat, Regulatordeacetylase) mocetinostat, givinostat, chidamide, quisinostat,abexinostat, chr-3996, ar-42, Brd4 INCN54329, INCB57643, Transcriptionbirabresib, apabetalone, regulator alvocidib, PLX-51107, FT-1101,RG-6146, AZD- 8186, CPI-0610, JQ1 HMT (histone Epigenetic methylRegulator transferases) LSD1 INCB59872, IMG-7289, RG-6016, EpigeneticCC-90011, GSK-2879552, ORY- Regulator 2001, 4SC-202, ORY-3001, TNFaRecombinant TNFa, MEDI-1873, Cytokine FPA-154, LKZ-145 IL1 RecombinantIL1 Cytokine IFNa Recombinant interferon alpha-n1, Cytokine Recombinantinterferon alpha-2b, Recombinant interferon alpha-n3 IFNb RecombinantIFN beta-1a, Cytokine IFNg actimmune Cytokine STING Cyclicdi-nucleotides Signaling Molecule TLR Poly I:C, IMO-2055, TMX-101,Pathogen imiquimod, CpG, MGN1703, Recognition glucopyranosyl lipid A,Receptor CBLB502, BCG, HILTONOL, AMPLIGEN, MOTOLIMOD, DUK-CPG-001, AS15IL10 Recombinant IL-10 Cytokine CCR2 CCX140, CCX872, BMS-813160,Chemokine CENICRIVIROC, CNTX-6970. PF-4136309, plozalizumab, INCB-9471,PF-04634817 CCR5 Maraviroc, PRO-140, Chemokine BMS-813160, NIFEVIROC,OHR-118 CXCR4 Ulocuplumab, plerixafor, Chemokine x4p-001, usl-311,ly-2510924, APH-0812, BL-8040, BURIXAFOR, BALIXAFORTIDE, PTX-9908,GMI-1359, F-50067 LFA1 Adhesion Molecule MICA/B IPH-4301 Immune ReceptorLigand VISTA CA-170 Checkpoint-Ligand Adenosine ISTRADEFYLLINE,Nucleoside TOZADENANT, PBF-509, PBF-999, CPI-444 CD39 OREG-103.Anti-CD39 Ecto-enzyme antibodies, CD73 Oleclumab, PBF-1662, Ecto-Enzymeanti-CD73 antibodies PD1 Pembrolizumab, nivolumab, Checkpoint-INCSHR1210, CT-011, AMP224 receptor PD-L1 Atezolizumab, avelumabCheckpoint- Ligand PD-L2 Checkpoint- Ligand CTLA4 TremelimumabCheckpoint- receptor CD137 Urelumab, utomilumab, BMS-663513, PF-05082566AXL BGB-324, BPI-9016M, S-49076 Kinase MERTK BGB-324, BPI-9016M, S-49076Kinase TYRO BGB-324, BPI-9016M, S-49076 BTK ibrutinib Kinase ITKibrutinib Kinase LCK Kinase TET2 Enzyme Arginase Cb-1158 Endo/ectoenzyme GCN2 Kinase B7-H4 MDX-1140, AMP-110 Checkpoint- receptorHIF1alpha PT2385 Transcription Factor LIGHT TNF (TNFSF14) SuperfamilyFLT3 CDX-301, FLX925, quizartinib, Kinase gilteritinib, PKC412,midostaurin, crenolanib CD158 Lirlumab, IPH-2101 CD47 Anti-CD47,TTI-621, NI-1701, SRF-231, Effi-DEM, RCT-1938 IDO Epacadostat, F287,BMS983205, GDC-0919, indoximod, RORgamma

In a further embodiment, the compounds described herein can beco-administered with conventional radiotherapeutic agents including, butnot limited to, radionuclides such as ⁴⁷Sc, ⁶⁴Cu, ⁶⁷Cu, ⁸⁹Sr, ⁸⁶Y, ⁸⁷Y,⁹⁰Y, ¹⁰⁵Rh, ¹¹¹Ag, ¹¹¹In, ^(117m)Sn, ¹⁴⁹Pm, ¹⁵³Sm, ¹⁶⁶Ho, ¹⁷⁷Lu, ¹⁸⁶Re,¹⁸⁸Re, ²¹¹At, and ²¹²Bi, optionally conjugated to antibodies directedagainst tumor antigens.

In addition, a CCR4 inhibitor may be combined with the therapeuticadministration of immune cells, sometimes referred to as adoptive celltransfer. These cells may be cells from the patient, a geneticallyrelated or unrelated donor, they may be genetically modified (e.g. CAR-Tcells, NK cells, etc), cell lines, genetically modified cell lines andlive or dead versions of the above. CCR4 inhibitors may also be combinedwith vaccines of any kind (e.g. protein/peptide, viral, bacterial,cellular) to stimulate immune responses to cancer.

In embodiments, treatment is administration of an effective amount of aCCR4 inhibitor in combination with an inhibitor of the PD-L1/PD-1pathway, an inhibitor of CTLA-4, an agonistic antibody of CD137 (4-1BB)or in combination with another immune modulator as listed in Table 1.

In embodiments, treatment is therapeutic administration of an effectiveamount of a CCR4 inhibitor in combination with an inhibitor of thePD-L1/PD-1 pathway, an inhibitor of CTLA-4, an agonistic antibody ofCD137 (4-1BB) or in combination with another immune modulator as listedin Table 1. Here, treatment starts when tumors reach a size of 40-70mm³.

The CCR4 inhibitors discloused herein can be administered by anyacceptable route, such oral, intraadiposal, intraarterial,intraarticular, intracranial, intradermal, intralesional, intramusculay,intranasal, intraocularal, intrapericardial, intraperitoneal,intrapleural, intraprostatical, intrarectal, intrathecal, intratracheal,intratumoral, intraumbilical, intravaginal, intravenousl,intravesicullar, intravitreal, liposomal, local, mucosal, parenteral,rectal, subconjunctival, subcutaneous, sublingual, topical, transbuccal,transdermal, vaginal, in cremes, in lipid compositions, via a catheter,via a lavage, via continuous infusion, via infusion, via inhalation, viainjection, via local delivery, via localized perfusion, bathing targetcells directly, or any combination thereof.

The immune modulators disclosed herein can be administered by anyacceptable route, such oral, intraadiposal, intraarterial,intraarticular, intracranial, intradermal, intralesional, intramusculay,intranasal, intraocularal, intrapericardial, intraperitoneal,intrapleural, intraprostatical, intrarectal, intrathecal, intratracheal,intratumoral, intraumbilical, intravaginal, intravenousl,intravesicullar, intravitreal, liposomal, local, mucosal, parenteral,rectal, subconjunctival, subcutaneous, sublingual, topical, transbuccal,transdermal, vaginal, in cremes, in lipid compositions, via a catheter,via a lavage, via continuous infusion, via infusion, via inhalation, viainjection, via local delivery, via localized perfusion, bathing targetcells directly, or any combination thereof.

The CCR4 inhibitors disclosed herein may be administered once dailyuntil study reached endpoint. The immune modulator disclosed herein maybe administered at least three times but in some studies four or moretimes depending on the length of the study and/or the design of thestudy.

The methods disclosed herein may be used in combination with additionalcancer therapy. In some embodiments, the distinct cancer therapycomprises surgery, radiotherapy, chemotherapy, toxin therapy,immunotherapy, cryotherapy or gene therapy. In some embodiments, thecancer is a chemotherapy-resistant or radio-resistant cancer.

A “cell” as used herein, refers to a cell carrying out metabolic orother function sufficient to preserve or replicate its genomic DNA. Acell can be identified by well-known methods in the art including, forexample, presence of an intact membrane, staining by a particular dye,ability to produce progeny or, in the case of a gamete, ability tocombine with a second gamete to produce a viable offspring. Cells mayinclude prokaryotic and eukaroytic cells. Prokaryotic cells include butare not limited to bacteria. Eukaryotic cells include but are notlimited to yeast cells and cells derived from plants and animals, forexample mammalian, insect (e.g., spodoptera) and human cells. Cells maybe useful when they are naturally nonadherent or have been treated notto adhere to surfaces, for example by trypsinization.

“Control” or “control experiment” is used in accordance with its plainordinary meaning and refers to an experiment in which the subjects orreagents of the experiment are treated as in a parallel experimentexcept for omission of a procedure, reagent, or variable of theexperiment. In some instances, the control is used as a standard ofcomparison in evaluating experimental effects. In some embodiments, acontrol is the measurement of the activity of a protein in the absenceof a compound as described herein (including embodiments and examples).

The term “modulator” refers to a composition that increases or decreasesthe level of a target molecule or the function of a target molecule orthe physical state of the target of the molecule. In some embodiments, aCCR4 associated disease modulator is a compound that reduces theseverity of one or more symptoms of a disease associated with CCR4 (e.g.cancer, inflammatory disease, autoimmune disease, or infectiousdisease). A CCR4 modulator is a compound that increases or decreases theactivity or function or level of activity or level of function of CCR4.A modulator may act alone, or it may use a cofactor, e.g., a protein,metal ion, or small molecule. Examples of modulators include smallmolecule compounds and other bioorganic molecules. Numerous libraries ofsmall molecule compounds (e.g., combinatorial libraries) arecommercially available and can serve as a starting point for identifyinga modulator. The skilled artisan is able to develop one or more assays(e.g., biochemical or cell-based assays) in which such compoundlibraries can be screened in order to identify one or more compoundshaving the desired properties; thereafter, the skilled medicinal chemistis able to optimize such one or more compounds by, for example,synthesizing and evaluating analogs and derivatives thereof. Syntheticand/or molecular modeling studies can also be utilized in theidentification of an activator

The term “modulate” is used in accordance with its plain ordinarymeaning and refers to the act of changing or varying one or moreproperties. “Modulation” refers to the process of changing or varyingone or more properties. For example, as applied to the effects of amodulator on a target protein, to modulate means to change by increasingor decreasing a property or function of the target molecule or theamount of the target molecule. In embodiments, the terms “modulate”,“modulation” and the like refer to the ability of a molecule (e.g., anactivator or an inhibitor) to increase or decrease the function oractivity of CCR4, either directly or indirectly, relative to the absenceof the molecule.

The term “associated” or “associated with” in the context of a substanceor substance activity or function associated with a disease (e.g. aprotein associated disease, a cancer associated with CCR4 activity, CCR4associated cancer, CCR4 associated disease (e.g., cancer, inflammatorydisease, autoimmune disease, or infectious disease)) means that thedisease (e.g. cancer, inflammatory disease, autoimmune disease, orinfectious disease) is caused by (in whole or in part), or a symptom ofthe disease is caused by (in whole or in part) the substance orsubstance activity or function. For example, a cancer associated withCCR4 activity or function may be a cancer that results (entirely orpartially) from aberrant CCR4 function (e.g. enzyme activity,protein-protein interaction, signaling pathway) or a cancer wherein aparticular symptom of the disease is caused (entirely or partially) byaberrant CCR4 activity or function. As used herein, what is described asbeing associated with a disease, if a causative agent, could be a targetfor treatment of the disease. For example, a cancer associated with CCR4activity or function or a CCR4 associated disease (e.g., cancer,inflammatory disease, autoimmune disease, or infectious disease), may betreated with a compound described herein (e.g., CCR4 modulator or CCR4inhibitor), in the instance where increased CCR4 activity or function(e.g. signaling pathway activity) causes the disease (e.g., cancer,inflammatory disease, autoimmune disease, or infectious disease). Forexample, an inflammatory disease associated with CCR4 activity orfunction or an CCR4 associated inflammatory disease, may be treated withan CCR4 modulator or CCR4 inhibitor, in the instance where increasedCCR4 activity or function (e.g. signaling pathway activity) causes thedisease.

The term “aberrant” as used herein refers to different from normal. Whenused to describe enzymatic activity or protein function, aberrant refersto activity or function that is greater or less than a normal control orthe average of normal non-diseased control samples. Aberrant activitymay refer to an amount of activity that results in a disease, whereinreturning the aberrant activity to a normal or non-disease-associatedamount (e.g. by administering a compound or using a method as describedherein), results in reduction of the disease or one or more diseasesymptoms.

The term “signaling pathway” as used herein refers to a series ofinteractions between cellular and optionally extra-cellular components(e.g. proteins, nucleic acids, small molecules, ions, lipids) thatconveys a change in one component to one or more other components, whichin turn may convey a change to additional components, which isoptionally propogated to other signaling pathway components. Forexample, binding of a CCR4 with a compound as described herein mayreduce the level of a product of the CCR4 catalyzed reaction or thelevel of a downstream derivative of the product or binding may reducethe interactions between the CCR4 or a reaction product and downstreameffectors or signaling pathway components (e.g., MAP kinase pathway),resulting in changes in cell growth, proliferation, or survival.

As used herein, the terms “CCR4 inhibitor”, “CCR4 antagonist”, “C—Cchemokine receptor type 4 inhibitor”, “C—C chemokine receptor type 4antagonist” and all other related art-accepted terms, many of which areset forth below, refer to a compound capable of modulating, eitherdirectly or indirectly, the CCR4 receptor in an in vitro assay, an invivo model, and/or other means indicative of therapeutic efficacy. Theterms also refer to a compound that exhibits at least some therapeuticbenefit in a human subject.

The phrase “in a sufficient amount to effect a change” means that thereis a detectable difference between a level of an indicator measuredbefore (e.g., a baseline level) and after administration of a particulartherapy. Indicators include any objective parameter (e.g., serumconcentration) or subjective parameter (e.g., a subject's feeling ofwell-being).

The “activity” of a molecule may describe or refer to the binding of themolecule to a ligand or to a receptor; to catalytic activity; to theability to stimulate gene expression or cell signaling, differentiation,or maturation; to antigenic activity; to the modulation of activities ofother molecules; and the like. The term “proliferative activity”encompasses an activity that promotes, that is necessary for, or that isspecifically associated with, for example, normal cell division, as wellas cancer, tumors, dysplasia, cell transformation, metastasis, andangiogenesis.

“Substantially pure” indicates that a component makes up greater thanabout 50% of the total content of the composition, and typically greaterthan about 60% of the total polypeptide content. More typically,“substantially pure” refers to compositions in which at least 75%, atleast 85%, at least 90% or more of the total composition is thecomponent of interest. In some cases, the polypeptide will make upgreater than about 90%, or greater than about 95% of the total contentof the composition (percentage in a weight per weight basis).

The terms “specifically binds” and “selectively binds,” when referringto a ligand/receptor, antibody/antigen, or other binding pair, indicatea binding reaction which is determinative of the presence of the proteinin a heterogeneous population of proteins and other biologics. Thus,under designated conditions, a specified ligand binds to a particularreceptor and does not bind in a significant amount to other proteinspresent in the sample. The antibody, or binding composition derived fromthe antigen-binding site of an antibody, of the contemplated methodbinds to its antigen, or a variant or mutein thereof, with an affinitythat is at least two-fold greater, at least 10-times greater, at least20-times greater, or at least 100-times greater than the affinity withany other antibody, or binding composition derived therefrom. Inembodiments, the antibody will have an affinity that is greater thanabout 10⁹ liters/mol, as determined by, e.g., Scatchard analysis(Munsen, et al. (1980) Analyt. Biochem. 107:220-239).

The terms “DNA,” “nucleic acid,” “nucleic acid molecule,”“polynucleotide” and the like are used interchangeably herein to referto a polymeric form of nucleotides of any length, eitherdeoxyribonucleotides or ribonucleotides, or analogs thereof.Non-limiting examples of polynucleotides include linear and circularnucleic acids, messenger RNA (mRNA), complementary DNA (cDNA),recombinant polynucleotides, vectors, probes, primers and the like.

As used herein, the terms “variants” and “homologs” are usedinterchangeably to refer to amino acid or nucleic acid sequences thatare similar to reference amino acid or nucleic acid sequences,respectively. The term encompasses naturally-occurring variants andnon-naturally-occurring variants. Naturally-occurring variants includehomologs (polypeptides and nucleic acids that differ in amino acid ornucleotide sequence, respectively, from one species to another), andallelic variants (polypeptides and nucleic acids that differ in aminoacid or nucleotide sequence, respectively, from one individual toanother within a species). Thus, variants and homologs encompassnaturally occurring amino acid and nucleic acid sequences encodedthereby and their isoforms, as well as splice variants of a protein orgene. The terms also encompass nucleic acid sequences that vary in oneor more bases from a naturally-occurring nucleic acid sequence but stilltranslate into an amino acid sequence that corresponds to thenaturally-occurring protein due to degeneracy of the genetic code.Non-naturally-occurring variants and homologs include polypeptides andnucleic acids that comprise a change in amino acid or nucleotidesequence, respectively, where the change in sequence is artificiallyintroduced (e.g., muteins); for example, the change is generated in thelaboratory by human intervention (“hand of man”). Therefore,non-naturally occurring variants and homologs may also refer to thosethat differ from the naturally occurring sequences by one or moreconservative substitutions and/or tags and/or conjugates.

The term “muteins” as used herein refers broadly to mutated recombinantproteins. These proteins usually carry single or multiple amino acidsubstitutions and are frequently derived from cloned genes that havebeen subjected to site-directed or random mutagenesis, or fromcompletely synthetic genes.

II. Compounds

In an aspect provided herein, is a compound having structural Formula(I):

or a pharmaceutically acceptable salt thereof. X¹ is CR⁸ or N. X² is CR⁹or N. X³ is CR¹⁰ or N. The symbols n1, n2, n3, n4, n5, n6, n7, n8, n9and n10 are independently an integer from 0 to 4. The symbols m1, m2,m3, m4, m5, m6, m7, m8, m9, m10, v1, v2, v3, v4, v5, v6, v7, v8, v9 andv10 are independently 1 or 2. The symbol z1 is an integer from 0 to 5.The symbol z2 is an integer from 0 to 5. In embodiments, z2 is aninteger from 0 to 2. The symbol z3 is an integer from 0 to 11. Inembodiments, the symbol z3 is an integer from 0 to 4. The symbol z4 isan integer from 0 to 2. L⁷ is a bond, —O—, —S—, —NR^(7.2B)—, —C(O)—,—C(O)O—, —S(O)—, —S(O)₂—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene. R¹ is hydrogen, halogen,—CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1), —CN, —N₃, —SO_(n1)R^(1A),—SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C), —ONR^(1B)R^(1C),—NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C), —N(O)_(m1),—NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A),—NR^(1B)SO₂R^(1A), —NR^(1B)C(O)R^(1D), —NR^(1B)C(O)OR^(1D),—NR^(1B)OR^(1D), —OCX^(1.1) ₃, —OCHX^(1.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R² is hydrogen, halogen, —CX^(2.1) ₃,—CHX^(2.1) ₂, —CH₂X^(2.1), —CN, —N₃, —SO_(n2)R^(2A),—SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C), —ONR^(2B)R^(2C),—NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C), —N(O)_(m2),—NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D), —C(O)NR^(2B)R^(2C), —OR^(2A),—NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D), —NR^(2B)C(O)OR^(2D),—NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R³ is independently hydrogen, halogen,—CX^(3.1) ₃, —CHX^(3.1) ₂, —CH₂X^(3.1), —CN, —N₃, —SO_(n3)R^(3A),—SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C), —ONR^(3B)R^(3C),—NHC(O)NHNR^(3B)R^(3C), —NHC(O)NR^(3B)R^(3C), —N(O)_(m3),—NR^(3B)R^(3C), —C(O)R^(3D), —C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A),—NR^(3B)SO₂R^(3A), —NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D),—NR^(3B)OR^(3D), —OCX^(3.1) ₃, —OCHX^(3.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl. R⁴ is hydrogen, halogen, —CX^(4.1) ₃,—CHX^(4.1) ₂, —CH₂X^(4.1), —CN, —N₃, —SO_(n4)R^(4A),—SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C), —ONR^(4B)R^(4C),—NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C), —N(O)_(m4),—NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D), —C(O)NR^(4B)R^(4C), —OR^(4A),—NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D), —NR^(4B)C(O)OR^(4D),—NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl. R⁵ is independently hydrogen, halogen, oxo,—CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —N₃, —SO_(n5)R^(5A),—SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), —ONR^(5B)R^(5C),—NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C), —N(O)_(m5),—NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A),—NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D),—NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl. R⁶ is independently hydrogen, halogen, oxo,—CX^(6.1) ₃, —CHX^(6.1) ₂, —CH₂X^(6.1), —CN, —N₃, —SO_(n6)R^(6A),—SO_(v6)NR^(6B)R^(6C), —NHNR^(6B)R^(6C), —ONR^(6B)R^(6C),—NHC(O)NHNR^(6B)R^(6C), —NHC(O)NR^(6B)R^(6C), —N(O)_(m6),—NR^(6B)R^(6C), —C(O)R^(6D), —C(O)OR^(6D), —C(O)NR^(6B)R^(6C), —OR^(6A),—NR^(6B)SO₂R^(6A), —NR^(6B)C(O)R^(6D), —NR^(6B)C(O)OR^(6D),—NR^(6B)OR^(6D), —OCX^(6.1) ₃, —OCHX^(6.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl. R⁷ is hydrogen, halogen, —CX^(7.1) ₃,—CHX^(7.1) ₂, —CH₂X^(7.1), —CN, —N₃, —SO_(n7)R^(7A),—SO_(v7)NR^(7B)R^(7C), —NHNR^(7B)R^(7C), —ONR^(7B)R^(7C),—NHC(O)NHNR^(7B)R^(7C), —NHC(O)NR^(7B)R^(7C), —N(O)_(m7),—NR^(7B)R^(7C), —C(O)R^(7D), —C(O)OR^(7D), —C(O)NR^(7B)R^(7C), —OR^(7A),—NR^(7B)SO₂R^(7A), —NR^(7B)C(O)R^(7D), —NR^(7B)C(O)OR^(7D),—NR^(7B)OR^(7D), —OCX^(7.1) ₃, —OCHX^(7.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl. R⁸ is hydrogen, halogen, —CX^(8.1) ₃,—CHX^(8.1) ₂, —CH₂X^(8.1), —CN, —N₃, —SO_(n8)R^(8A),—SO_(v8)NR^(8B)R^(8C), —NHNR^(8B)R^(8C), —ONR^(8B)R^(8C),—NHC(O)NHNR^(8B)R^(8C), —NHC(O)NR^(8B)R^(8C), —N(O)_(m8),—NR^(8B)R^(8C), —C(O)R^(8D), —C(O)OR^(8D), —C(O)NR^(8B)R^(8C), —OR^(8A),—NR^(8B)SO₂R^(8A), —NR^(8B)C(O)R^(8D), —NR^(8B)C(O)OR^(8D),—NR^(8B)OR^(8D), —OCX^(8.1) ₃, —OCHX^(8.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R⁹ is hydrogen, halogen, —CX^(9.1) ₃,—CHX^(9.1) ₂, —CH₂X^(9.1), —CN, —N₃, —SO_(n9)R^(9A),—SO_(v9)NR^(9B)R^(9C), —NHNR^(9B)R^(9C), —ONR^(9B)R^(9C),—NHC(O)NHNR^(9B)R^(9C), —NHC(O)NR^(9B)R^(9C), —N(O)_(m9),—NR^(9B)R^(9C), —C(O)R^(9D), —C(O)OR^(9D), —C(O)NR^(9B)R^(9C), —OR^(9A),—NR^(9B)SO₂R^(9A), —NR^(9B)C(O)R^(9D), —NR^(9B)C(O)OR^(9D),—NR^(9B)OR^(9D), —OCX^(9.1) ₃, —OCHX^(9.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R¹⁰ is hydrogen, halogen, —CX^(10.1) ₃,—CHX^(10.1) ₂, —CH₂X^(10.1), —CN, —SO_(n10)R^(10A),—SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C), —ONR^(10B)R^(10C),—NHC(O)NHNR^(10B)R^(10C), —NHC(O)NR^(10B)R^(10C), —N(O)_(m10),—NR^(10B)R^(10C), —C(O)R^(10D), —C(O)OR^(10D), —C(O)NR^(10B)R^(10C),—OR^(10A), —NR^(10B)SO₂R^(10A), —NR^(10B)C(O)R^(10D),—NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D), —OCX^(10.1) ₃, —OCHX^(10.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R^(1A), R^(1B), R^(1C), R^(1D),R^(2A), R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(3C), R^(3D), R^(4A),R^(4B), R^(4C), R^(4D), R^(5A), R^(5B), R^(5C), R^(5D), R^(6A), R^(6B),R^(6C), R^(6D), R^(7A), R^(7B), R^(7C), R^(7D), R^(7.2B), R^(8A),R^(8B), R^(8C), R^(8D), R^(9A), R^(9B), R^(9C), R^(9D), R^(10A),R^(10B), R^(10C) and R^(10D) are independently hydrogen, halogen, —CF₃,—CCl₃, —CBr₃, —CI₃, —COOH, —CONH₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(1B), R^(1C), R^(2B), R^(2C), R^(3B), R^(3C), R^(4B), R^(4C), R^(5B),R^(5C), R^(6B), R^(6C), R^(7B), R^(7C), R^(8B), R^(8C), R^(9B), R^(9C),R^(10B) and R^(10C) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl. X^(1.1),X^(2.1), X^(3.1), X^(4.1), X^(5.1), X^(6.1), X^(7.1), X^(8.1), X^(9.1)and X^(10.1) are independently —Cl, —Br, —I, or —F, wherein at least oneof X¹, X² and X³ is N.

In embodiments, X¹ is CR⁸. In embodiments, X² is CR⁹. In embodiments, X³is CR¹⁰. In embodiments, X¹ is N. In embodiments, X² is N. Inembodiments, X³ is N.

In embodiments, R¹ is halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1),—CN, —N₃, —SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C),—ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C),—N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D),—C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A), —NR^(1B)C(O)R^(1D),—NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃, —OCHX^(1.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. In embodiments, R¹ is hydrogen.

In embodiments, R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂,—CH₂X^(1.1), —CN, —N₃, —SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C),—NHNR^(1B)R^(1C), —ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C),—NHC(O)NR^(1B)R^(1C), —N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D),—C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A),—NR^(1B)C(O)R^(1D), —NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃,—OCHX^(1.1) ₂, R¹¹-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R¹¹-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R¹¹-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), R¹¹-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R¹¹-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR¹¹-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹ is R¹¹-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹ isR¹¹-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R¹ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R¹ is R¹¹-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R¹ is R¹¹-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R¹ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R¹ is R¹¹-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R¹ is R¹¹-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R¹ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R¹ is R¹¹-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R¹ is R¹¹-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R¹ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R¹ is R¹¹-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹ is R¹¹-substitutedaryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹ is anunsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

In embodiments, R¹ is R¹¹-substituted or unsubstituted heteroaryl (e.g.,5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R¹ is R¹¹-substituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R¹ is an unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R² is halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1),—CN, —N₃, —SO_(n2)R^(2A), —SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C),—ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C),—N(O)_(m2), —NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D),—C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D),—NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. In embodiments, R² is hydrogen.

In embodiments, R² is halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1),—CN, —N₃, —SO_(n2)R^(2A), —SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C),—ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C),—N(O)_(m2), —NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D),—C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D),—NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂,R¹⁴-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), R¹⁴-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4membered heteroalkyl), R¹⁴-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R¹⁴-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), R¹⁴-substituted or unsubstituted aryl (e.g., C₆-C₁₀aryl, C₁₀ aryl, or phenyl), or R¹⁴-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R² is R¹⁴-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R² isR¹⁴-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R² is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). In embodiments, R² is an unsubstituted ethyl. Inembodiments, R² is an unsubstituted C₃ alkyl. In embodiments, R² is anunsubstituted C₄ alkyl.

In embodiments, R² is R¹⁴-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R² is R¹⁴-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R² is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R² is R¹⁴-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R² is R¹⁴-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R² is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R² is R¹⁴-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R² is R¹⁴-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R² is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R² is R¹⁴-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R² is R¹⁴-substitutedaryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R² is anunsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

In embodiments, R² is R¹⁴-substituted or unsubstituted heteroaryl (e.g.,5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R² is R¹⁴-substituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R² is an unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R³ is independently halogen, —CX^(3.1) ₃, —CHX^(3.1) ₂,—CH₂X^(3.1), —CN, —N₃, —SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C),—NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),—NHC(O)NR^(3B)R^(3C), —N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D),—C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A),—NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃,—OCHX^(3.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl. Inembodiments, R³ is hydrogen.

In embodiments, R³ is independently halogen, —CX^(3.1) ₃, —CHX^(3.1) ₂,—CH₂X^(3.1), —CN, —N₃, —SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C),—NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),—NHC(O)NR^(3B)R^(3C), —N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D),—C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A),—NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃,—OCHX^(3.1) ₂, R¹⁷-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R¹⁷-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R¹⁷-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), R¹⁷-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R¹⁷-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR¹⁷-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R³ is independently R¹⁷-substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R³ is independently R¹⁷-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). In embodiments, R³ is independently anunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

In embodiments, R³ is independently R¹⁷-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R³ isindependently R¹⁷-substituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl). In embodiments, R³ is independently an unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R³ is independently R¹⁷-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl). In embodiments, R³ is independently R¹⁷-substitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl). In embodiments, R³ is independently an unsubstitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl).

In embodiments, R³ is independently R¹⁷-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, R³ is independently R¹⁷-substituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl). In embodiments, R³ is independently anunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R³ is independently R¹⁷-substituted or unsubstitutedaryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R³ isindependently R¹⁷-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl). In embodiments, R³ is independently an unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

In embodiments, R³ is independently R¹⁷-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R³ isindependently R¹⁷-substituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R³ is independently an unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, the definition of R³ is assumed by (independentlyassigned to) R^(3.1), R^(3.2), R³³, R^(3.4), R^(3.5).

In embodiments, R^(3.2) is halogen, —CX^(3.2) ₃, —CHX^(3.2) ₂,—CH₂X^(3.2), —CN, —N₃, —SO_(n3.2)R^(3.2A), —SO_(v3.2)NR^(3.2B)R^(3.2C),—NHNR^(3.2B)R^(3.2C), —ONR^(3.2B)R^(3.2C), —NHC(O)NHNR^(3.2B)R^(3.2C),—NHC(O)NR^(3.2B)R^(3.2C), —N(O)_(m3.2), —NR^(3.2B)R^(3.2C),—C(O)R^(3.2D), —C(O)OR^(3.2D), —C(O)NR^(3.2B)R^(3.2C), —OR^(3.2A),—NR^(3.2B)SO₂R^(3.2A), —NR^(3.2B)C(O)R^(3.2D), —NR^(3.2B)C(O)OR^(3.2D),—NR^(3.2B)OR^(3.2D), —OCX^(3.2) ₃, —OCHX^(3.2) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl. X^(3.2) is halogen. In embodiments, R^(3.2) ishydrogen. In embodiments, R^(3.2) is halogen. In embodiments, R^(3.2) ischlorine.

In embodiments, R^(3.2) is hydrogen, halogen, —CX^(3.2) ₃, —CHX^(3.2) ₂,—CH₂X^(3.2), —CN, —N₃, —SO_(n3.2)R^(3.2A), —SO_(v3.2)NR^(3.2B)R^(3.2C),—NHNR^(3.2B)R^(3.2C), —ONR^(3.2B)R^(3.2C), —NHC(O)NHNR^(3.2B)R^(3.2C),—NHC(O)NR^(3.2B)R^(3.2C), —N(O)_(m3.2), —NR^(3.2B)R^(3.2C),—C(O)R^(3.2D), —C(O)OR^(3.2D), —C(O)NR^(3.2B)R^(3.2C), —OR^(3.2A),—NR^(3.2B)SO₂R^(3.2A), —NR^(3.2B)C(O)R^(3.2D), —NR^(3.2B)C(O)OR^(3.2D),—NR^(3.2B)OR^(3.2D), —OCX^(3.2) ₃, —OCHX^(3.2) ₂, R^(17.2)-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R^(17.2)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R^(17.2)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(17.2)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(17.2)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(17.2)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(3.2) is R^(17.2)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R^(3.2) is R^(17.2)-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl). In embodiments, R^(3.2) is an unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

In embodiments, R^(3.2) is R^(17.2)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R^(3.2) isR^(17.2)-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). Inembodiments, R^(3.2) is an unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl).

In embodiments, R^(3.2) is R^(17.2)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl). In embodiments, R^(3.2) is R^(17.2)-substituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R^(3.2) is an unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

In embodiments, R^(3.2) is R^(17.2)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, R^(3.2) is R^(17.2)-substituted heterocycloalkyl (e.g., 3to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl). In embodiments, R^(3.2) is anunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R^(3.2) is R^(17.2)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R^(3.2) isR^(17.2)-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R^(3.2) is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl, or phenyl).

In embodiments, R^(3.2) is R^(17.2)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R^(3.2) isR^(17.2)-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments,R^(3.2) is an unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R³³ is, halogen, —CX³³ ₃, —CHX³³ ₂, —CH₂X³³, —CN, —N₃,—SO_(n3.3)R^(33A), —SO_(v3.3)NR^(33B)R^(33C), —NHNR^(33B)R^(33C),—ONR^(33B)R^(33C), —NHC(O)NHNR^(3.3B)R^(3.3C), —NHC(O)NR^(33B)R^(33C),—N(O)_(m3.3), —NR^(33B)R^(33C), —C(O)R^(33D), —C(O)OR^(33D),—C(O)NR^(3.3B)R^(3.3C), —OR^(33A), —NR^(33B)SO₂R^(33A),—NR^(33B)C(O)R^(33D), —NR^(33B)C(O)OR^(33D), —NR^(33B)OR^(33D), —OCX³³₃, —OCHX³³ ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl. X³³ ishalogen. In embodiments, R³³ is hydrogen. In embodiments, R³³ ishalogen. In embodiments, R³³ is chlorine.

In embodiments, R³³ is hydrogen, halogen, —CX^(3.3) ₃, —CHX³³ ₂,—CH₂X^(3.3), —CN, —N₃, —SO_(n3.3)R^(3.3A), —SO_(v3.3)NR^(33B)R^(33C),—NHNR^(33B)R^(33C), —ONR^(33B)R^(33C), —NHC(O)NHNR^(3.3B)R^(3.3C),—NHC(O)NR^(33B)R^(33C), —N(O)_(m3.3), —NR^(33B)R^(33C), —C(O)R^(33D),—C(O)OR^(33D), —C(O)NR^(3.3B)R^(3.3C), —OR^(33A), —NR^(33B)SO₂R^(33A),—NR^(33B)C(O)R^(33D), —NR^(33B)C(O)OR^(33D), —NR^(33B)OR^(33D), —OCX³³₃, —OCHX^(3.3) ₂, R^(17.3)-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(17.3)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(17.3)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(17.3)-substitutedor unsubstituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), R^(17.3)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(17.3)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(3.3) is R^(17.3)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R^(3.3) is R^(17.3)-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl). In embodiments, R^(3.3) is an unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

In embodiments, R^(3.3) is R^(17.3)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R^(3.3) isR^(17.3)-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). Inembodiments, R^(3.3) is an unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl).

In embodiments, R^(3.3) is R^(17.3)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl). In embodiments, R^(3.3) is R^(17.3)-substituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R^(3.3) is an unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

In embodiments, R^(3.3) is R^(17.3)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, R^(3.3) is R^(17.3)-substituted heterocycloalkyl (e.g., 3to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl). In embodiments, R^(3.3) is anunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R³³ is R^(17.3)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R³³ isR^(17.3)-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R³³ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R³³ is R^(17.3)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R³³ is R^(17.3)-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R³³ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R⁴ is halogen, —CX^(4.1) ₃, —CHX^(4.1) ₂, —CHX₂X^(4.1),—CN, —N₃, —SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C),—ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C),—N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D),—C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D),—NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl. In embodiments, R⁴ is hydrogen.

In embodiments, R⁴ is halogen, —CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1),—CN, —N₃, —SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C),—ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C),—N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D),—C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D),—NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), OCX^(4.1) ₃, —OCHX^(4.1) ₂,R²⁰-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), R²⁰-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4membered heteroalkyl), R²⁰-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R²⁰-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), R²⁰-substituted or unsubstituted aryl (e.g., C₆-C₁₀aryl, C₁₀ aryl, or phenyl), or R²⁰-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R⁴ is —CN.In embodiments, R⁴ is —C(O)NH₂. In embodiments, R⁴ is —CF₃. Inembodiments, R⁴ is —CH₃.

In embodiments, R⁴ is R²⁰-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁴ isR²⁰-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R⁴ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). In embodiments, R⁴ is an unsubstituted ethyl. Inembodiments, R⁴ is an unsubstituted C₃ alkyl. In embodiments, R⁴ is anunsubstituted C₄ alkyl.

In embodiments, R⁴ is R²⁰-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R⁴ is R²⁰-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R⁴ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R⁴ is R²⁰-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R⁴ is R²⁰-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R⁴ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R⁴ is R²⁰-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R⁴ is R²⁰-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R⁴ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R⁴ is R²⁰-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁴ is R²⁰-substitutedaryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁴ is anunsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

In embodiments, R⁴ is R²⁰-substituted or unsubstituted heteroaryl (e.g.,5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R⁴ is R²⁰-substituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R⁴ is an unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R⁵ is independently halogen, oxo, —CX^(5.1) ₃,—CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —N₃, —SO_(n5)R^(5A),—SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), —ONR^(5B)R^(5C),—NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C), —N(O)_(m5),—NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A),—NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D),—NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl. In embodiments, R⁵ is hydrogen.

In embodiments, R⁵ is independently halogen, —CX^(5.1) ₃, —CHX^(5.1) ₂,—CH₂X^(5.1), —CN, —N₃, —SO_(n5)R^(5A), —SO_(v5)NR^(5B)R^(5C),—NHNR^(5B)R^(5C), —ONR^(5B)R^(5C), —NHC(O)NHNR^(5B)R^(5C),—NHC(O)NR^(5B)R^(NC), —N(O)_(m5), —NR^(5B)R^(5C), —C(O)R^(5D),—C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A), —NR^(5B)SO₂R^(5A),—NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D), —NR^(5B)OR^(5D), —OCX^(5.1) ₃,—OCHX^(5.1) ₂, R²³-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²³-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R²³-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), R²³-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²³-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR²³-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R⁵ is independently R²³-substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R⁵ is independently R²³-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). In embodiments, R⁵ is independently anunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

In embodiments, R⁵ is independently R²³-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R⁵ isindependently R²³-substituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl). In embodiments, R⁵ is independently an unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R⁵ is independently R²³-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl). In embodiments, R⁵ is independently R²³-substitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl). In embodiments, R⁵ is independently an unsubstitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl).

In embodiments, R⁵ is independently R²³-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, R⁵ is independently R²³-substituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl). In embodiments, R⁵ is independently anunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R⁵ is independently R²³-substituted or unsubstitutedaryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁵ isindependently R²³-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl). In embodiments, R⁵ is independently an unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

In embodiments, R⁵ is independently R²³-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R⁵ isindependently R²³-substituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R⁵ is independently an unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R⁶ is independently halogen, oxo, —CX^(6.1) ₃,—CHX^(6.1) ₂, —CH₂X^(6.1), —CN, —N₃, —SO_(n6)R^(6A),—SO_(v6)NR^(6B)R^(6C), —NHNR^(6B)R^(6C), —ONR^(6B)R^(6C),—NHC(O)NHNR^(6B)R^(6C), —NHC(O)NR^(6B)R^(6C), —N(O)_(m6),—NR^(6B)R^(6C), —C(O)R^(6D), —C(O)OR^(6D), —C(O)NR^(6B)R^(6C), —OR^(6A),—NR^(6B)SO₂R^(6A), —NR^(6B)C(O)R^(6D), —NR^(6B)C(O)OR^(6D),—NR^(6B)OR^(6D), —OCX^(6.1) ₃, —OCHX^(6.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl. In embodiments, R⁶ is hydrogen.

In embodiments, R⁶ is independently halogen, —CX^(6.1) ₃, —CHX^(6.1) ₂,—CH₂X^(6.1), —CN, —N₃, —SO_(n6)R^(6A), —SO_(v6)NR^(6B)R^(6C),—NHNR^(6B)R^(6C), —ONR^(6B)R^(6C), —NHC(O)NHNR^(6B)R^(6C),—NHC(O)NR^(6B)R^(6C), —N(O)_(m6), —NR^(6B)R^(6C), —C(O)R^(6D),—C(O)OR^(6D), —C(O)NR^(6B)R^(6C), —OR^(6A), —NR^(6B)SO₂R^(6A),—NR^(6B)C(O)R^(6D), —NR^(6B)C(O)OR^(6D), —NR^(6B)OR^(6D), —OCX^(6.1) ₃,—OCHX^(6.1) ₂, R²⁶-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²⁶-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R²⁶-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), R²⁶-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²⁶-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR²⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R⁶ is hydrogen. In embodiments, R⁶ is R²⁶-substituted orunsubstituted alkyl. In embodiments, R⁶ is unsubstituted phenyl. Inembodiments, R⁶ is —F. In embodiments, R⁶ is —OH. In embodiments, R⁶ is—CH₂OH. In embodiments, R⁶ is —(CH₂)₂OH. In embodiments, R⁶ is—(CH₂)₃OH. In embodiments, R⁶ is —C(CH₃)₂OH. In embodiments, R⁶ is—CH₂SO₂NH₂. In embodiments, R⁶ is —(CH₂)₂SO₂NH₂. In embodiments, R⁶ is—CH₂C(O)NH₂. In embodiments, R⁶ is —(CH₂)₂C(O)NH₂. In embodiments, R⁶ is—(CH₂)₃C(O)NH₂. In embodiments, R⁶ is —CH₂NHSO₂CF₃. In embodiments, R⁶is —(CH₂)₂NHSO₂CF₃. In embodiments, R⁶ is —(CH₂)₃NHSO₂CF₃. Inembodiments, R⁶ is —CH₂NHSO₂CH₃. In embodiments, R⁶ is —(CH₂)₂NHSO₂CH₃.In embodiments, R⁶ is —(CH₂)₃NHSO₂CH₃. In embodiments, R⁶ is —CH₂SO₂CH₃.In embodiments, R⁶ is —(CH₂)₂SO₂CH₃. In embodiments, R⁶ is —CH₂SO₂NH₂.In embodiments, R⁶ is —(CH₂)₂SO₂NH₂.

In embodiments, R⁶ is independently R²⁶-substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R⁶ is independently R²⁶-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). In embodiments, R⁶ is independently anunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

In embodiments, R⁶ is independently R²⁶-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R⁶ isindependently R²⁶-substituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl). In embodiments, R⁶ is independently an unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R⁶ is independently R²⁶-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl). In embodiments, R⁶ is independently R²⁶-substitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl). In embodiments, R⁶ is independently an unsubstitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl).

In embodiments, R⁶ is independently R²⁶-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, R⁶ is independently R²⁶-substituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl). In embodiments, R⁶ is independently anunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R⁶ is independently R²⁶-substituted or unsubstitutedaryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁶ isindependently R²⁶-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl). In embodiments, R⁶ is independently an unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

In embodiments, R⁶ is independently R²⁶-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R⁶ isindependently R²⁶-substituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R⁶ is independently an unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R⁷ is halogen, —CX^(7.1) ₃, —CHX^(7.1) ₂, —CH₂X^(7.1),—CN, —N₃, —SO_(n7)R^(7A), —SO_(v7)NR^(7B)R^(7C), —NHNR^(7B)R^(7C),—ONR^(7B)R^(7C), —NHC(O)NHNR^(7B)R^(7C), —NHC(O)NR^(7B)R^(7C),—N(O)_(m7), —NR^(7B)R^(7C), —C(O)R^(7D), —C(O)OR^(7D),—C(O)NR^(7B)R^(7C), —OR^(7A), —NR^(7B)SO₂R^(7A), —NR^(7B)C(O)R^(7D),—NR^(7B)C(O)OR^(7D), —NR^(7B)OR^(7D), —OCX^(7.1) ₃, —OCHX^(7.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl. In embodiments, R⁷ is hydrogen.In embodiments, R⁷ is —C(O)OH. In embodiments, R⁷ is —OH. Inembodiments, R⁷ is —NH₂. In embodiments, R⁷ is —C(O)NH₂.

In embodiments, R⁷ is halogen, —CX^(7.1) ₃, —CHX^(7.1) ₂, —CH₂X^(7.1),—CN, —N₃, —SO_(n7)R^(7A), —SO_(v7)NR^(7B)R^(7C), —NHNR^(7B)R^(7C),—ONR^(7B)R^(7C), —NHC(O)NHNR^(7B)R^(7C), —NHC(O)NR^(7B)R^(7C),—N(O)_(m7), —NR^(7B)R^(7C), —C(O)R^(7D), —C(O)OR^(7D),—C(O)NR^(7B)R^(7C), —OR^(7A), —NR^(7B)SO₂R^(7A), —NR^(7B)C(O)R^(7D),—NR^(7B)C(O)OR^(7D), —NR^(7B)OR^(7D), —OCX^(7.1) ₃, —OCHX^(7.1) ₂,R²⁹-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), R²⁹-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4membered heteroalkyl), R²⁹-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R²⁹-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), R²⁹-substituted or unsubstituted aryl (e.g., C₆-C₁₀aryl, C₁₀ aryl, or phenyl), or R²⁹-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R⁷ is —(CH₂)₃COOH. In embodiments, R⁷ is —(CH₂)₂COOH. Inembodiments, R⁷ is —(CH₂)₁COOH. In embodiments, R⁷ is —(CH₂)₂CONH₂. Inembodiments, R⁷ is —(CH₂)₃CONH₂. In embodiments, R⁷ is —(CH₂)₃OH. Inembodiments, R⁷ is substituted cyclobutyl. In embodiments, R⁷ is—(CH₂)₂SO₂CH₃. In embodiments, R⁷ is —CH₂CH(CH₃)OH. In embodiments, R⁷is —(CH₂)₂OH. In embodiments, R⁷ is —(CH₂)₄OH. In embodiments, R⁷ is—(CH₂)₁OH. In embodiments, R⁷ is —(CH₂)₂NHSO₂CH₃. In embodiments, R⁷ is—(CH₂)₂NHSO₂CH₂CH₃. In embodiments, R⁷ is —(CH₂)₂NHSO₂(CH₂)₂CH₃. Inembodiments, R⁷ is —(CH₂)₂NHSO₂CH(CH₃)₂. In embodiments, R⁷ is—(CH₂)₂NHC(O)OCH₃. In embodiments, R⁷ is —(CH₂)₃SO₂CH₃. In embodiments,R⁷ is —(CH₂)₂NHC(O)CH₃. In embodiments, R⁷ is —(CH₂)₂NHC(O)H. Inembodiments, R⁷ is —CH₂C(O)OCH₃. In embodiments, R⁷ is —CH₂C(O)OCH₂CH₃.In embodiments, R⁷ is —(CH₂)₃SO₂NH_(2.) In embodiments, R⁷ is—(CH₂)₂SO₂NH₂. In embodiments, R⁷ is —(CH₂)₁SO₂NH₂. In embodiments, R⁷is —(CH₂)₂NHC(O)CH₂CH₃. In embodiments, R⁷ is —(CH₂)₂NHC(O)CH(CH₃)₂.

In embodiments, R⁷ is hydrogen. In embodiments, R⁷ is R²⁹-substituted orunsubstituted alkyl. In embodiments, R⁷ is phenyl. In embodiments, R⁷ is—(CH₂)₂OH. In embodiments, R⁷ is —CH₂C(CH₃)₂OH. In embodiments, R⁷ is—(CH₂)₃OH. In embodiments, R⁷ is —(CH₂)₂CH(CH₃)₂OH. In embodiments, R⁷is —(CH₂)₂SO₂NH₂. In embodiments, R⁷ is —(CH₂)₃SO₂NH₂. In embodiments,R⁷ is —(CH₂)₂CONH₂. In embodiments, R⁷ is —(CH₂)₃CONH₂. In embodiments,R⁷ is —(CH₂)₃CON(H)Me. In embodiments, R⁷ is —(CH₂)₃CON(Me)₂. Inembodiments, R⁷ is —(CH₂)₂SO₂Me. In embodiments, R⁷ is —(CH₂)₃SO₂Me. Inembodiments, R⁷ is —CH₂CH(OH)Me. In embodiments, R⁷ is —CH₂CO₂H. Inembodiments, R⁷ is —(CH₂)₂CO₂H. In embodiments, R⁷ is —CH(CH₃)CH₂CO₂H.In embodiments, R⁷ is —(CH₂)₃CO₂H. In embodiments, R⁷ is—(CH₂)₂SO₂NHCH₃. In embodiments, R⁷ is —(CH₂)₂SO₂N(CH₃)₂. Inembodiments, R⁷ is —(CH₂)₂SO₂-(N-morpholinyl). In embodiments, R⁷ is—(CH₂)₂NHCOCH₃. In embodiments, R⁷ is —(CH₂)₂NHC(O)OCH₃. In embodiments,R⁷ is —(CH₂)₃NHCOCH₃. In embodiments, R⁷ is —(CH₂)₂NHCOCH(CH₃)₂. Inembodiments, R⁷ is —(CH₂)₂NHSO₂CH₃. In embodiments, R⁷ is—(CH₂)₂NHSO₂CF₃. In embodiments, R⁷ is —(CH₂)₂NHSO₂NHCH(CH₃)₂. Inembodiments, R⁷ is —CH₂CH(CH₃)CH₂OH (R and S). In embodiments, R⁷ is—CH(CH₃)(CH₂)₂OH. In embodiments, R⁷ is —CH₂-(2-imidazoyl). Inembodiments, R⁷ is —CH₂-(4-imidazoyl). In embodiments, R⁷ is—CH₂-(3-pyrazoyl). In embodiments, R⁷ is 4-tetrahydropyranyl. Inembodiments, R⁷ is 3-oxetanyl. In embodiments, R⁷ is —(CH₂)₂NHCO₂Me. Inembodiments, R⁷ is —(CH₂)₃NHCO₂Me.

In embodiments, R⁷ is hydrogen, R²⁹-substituted or unsubstituted alkyl,phenyl, —F, —OH, CH₂OH, —(CH₂)₂OH, —(CH₂)₃OH, —C(CH₃)₂OH, —CH₂SO₂NH₂,—(CH₂)₂SO₂NH₂, —CH₂C(O)NH₂, —(CH₂)₂C(O)NH₂, —(CH₂)₃C(O)NH₂,—CH₂NHSO₂CF₃, —(CH₂)₂NHSO₂CF₃, —(CH₂)₃NHSO₂CF₃, —CH₂NHSO₂CH₃,—(CH₂)₂NHSO₂CH₃, —(CH₂)₃NHSO₂CH₃, —CH₂SO₂CH₃, —(CH₂)₂SO₂CH₃, —CH₂SO₂NH₂or —(CH₂)₂SO₂NH₂.

In embodiments, R⁷ is R²⁹-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁷ isR²⁹-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R⁷ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). In embodiments, R⁷ is an unsubstituted C₁-C₄alkyl. In embodiments, R⁷ is an unsubstituted C₁-C₃ alkyl. Inembodiments, R⁷ is an unsubstituted C₁-C₂ alkyl. In embodiments, R⁷ isan unsubstituted C₄ alkyl. In embodiments, R⁷ is an unsubstituted C₃alkyl. In embodiments, R⁷ is a R²⁷-substituted alkyl (e.g., C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁷ is a R²⁷-substitutedC₁-C₄ alkyl. In embodiments, R⁷ is a R²⁷-substituted C₁-C₃ alkyl. Inembodiments, R⁷ is a R²⁷-substituted C₁-C₂ alkyl. In embodiments, R⁷ isa R²⁷-substituted C₄ alkyl. In embodiments, R⁷ is a R²⁷-substituted C₃alkyl.

In embodiments, R⁷ is R²⁹-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R⁷ is R²⁹-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R⁷ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R⁷ is R²⁹-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R⁷ is R²⁹-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R⁷ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl). In embodiments, R⁷ is an unsubstituted C₃-C₆cycloalkyl. In embodiments, R⁷ is an unsubstituted C₃-C₅ cycloalkyl. Inembodiments, R⁷ is an unsubstituted C₃-C₄ cycloalkyl. In embodiments, R⁷is an unsubstituted C₄ cycloalkyl. In embodiments, R⁷ is aR²⁹-substituted C₃-C₆ cycloalkyl. In embodiments, R⁷ is aR²⁹-substituted C₃-C₅ cycloalkyl. In embodiments, R⁷ is aR²⁹-substituted C₃-C₄ cycloalkyl. In embodiments, R⁷ is aR²⁹-substituted C₄ cycloalkyl.

In embodiments, R⁷ is R²⁹-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R⁷ is R²⁹-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R⁷ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R⁷ is R²⁹-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁷ is R²⁹-substitutedaryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁷ is anunsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

In embodiments, R⁷ is R²⁹-substituted or unsubstituted heteroaryl (e.g.,5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R⁷ is R²⁹-substituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R⁷ is an unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R⁸ is halogen, —CX^(8.1) ₃, —CHX^(8.1) ₂, —CH₂X^(8.1),—CN, —N₃, —SO_(n8)R^(8A), —SO_(v8)NR^(8B)R^(8C), —NHNR^(8B)R^(8C),—ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C), —NHC(O)NR^(8B)R^(8C),—N(O)_(m8), —NR^(8B)R^(8C), —C(O)R^(8D), —C(O)OR^(8D),—C(O)NR^(8B)R^(8C), —OR^(8A), —NR^(8B)SO₂R^(8A), —NR^(8B)C(O)R^(8D),—NR^(8B)C(O)OR^(8D), —NR^(8B)OR^(8D), —OCX^(8.1) ₃, —OCHX^(8.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. In embodiments, R⁸ is hydrogen.

In embodiments, R⁸ is halogen, —CX^(8.1) ₃, —CHX^(8.1) ₂, —CH₂X^(8.1),—CN, —N₃, —SO_(n8)R^(8A), —SO_(v8)NR^(8B)R^(8C), —NHNR^(8B)R^(8C),—ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C), —NHC(O)NR^(8B)R^(8C),—N(O)_(m8), —NR^(8B)R^(8C), —C(O)R^(8D), —C(O)OR^(8D),—C(O)NR^(8B)R^(8C), —OR^(8A), —NR^(8B)SO₂R^(8A), —NR^(8B)C(O)R^(8D),—NR^(8B)C(O)OR^(8D), —NR^(8B)OR^(8D), —OCX^(8.1) ₃, —OCHX^(8.1) ₂,R³²-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), R³²-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4membered heteroalkyl), R³²-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R³²-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), R³²-substituted or unsubstituted aryl (e.g., C₆-C₁₀aryl, C₁₀ aryl, or phenyl), or R³²-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R⁸ is R³²-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁸ isR³²-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R⁸ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R⁸ is R³²-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R⁸ is R³²-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R⁸ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R⁸ is R³²-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R⁸ is R³²-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R⁸ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R⁸ is R³²-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R⁸ is R³²-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R⁸ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R⁸ is R³²-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁸ is R³²-substitutedaryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁸ is anunsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

In embodiments, R⁸ is R³²-substituted or unsubstituted heteroaryl (e.g.,5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R⁸ is R³²-substituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R⁸ is an unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R⁹ is halogen, —CX^(9.1) ₃, —CHX^(9.1) ₂, —CH₂X^(9.1),—CN, —N₃, —SO_(n9)R^(9A), —SO_(v9)NR^(9B)R^(9C), —NHNR^(9B)R^(9C),—ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C), —NHC(O)NR^(9B)R^(9C),—N(O)_(m9), —NR^(9B)R^(9C), —C(O)R^(9D), —C(O)OR^(9D),—C(O)NR^(9B)R^(9C), —OR^(9A), —NR^(9B)SO₂R^(9A), —NR^(9B)C(O)R^(9D),—NR^(9B)C(O)OR^(9D), —NR^(9B)OR^(9D), —OCX^(9.1) ₃, —OCHX^(9.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. In embodiments, R⁹ is hydrogen.

In embodiments, R⁹ is halogen, —CX^(9.1) ₃, —CHX^(9.1) ₂, —CH₂X^(9.1),—CN, —N₃, —SO_(n9)R^(9A), —SO_(v9)NR^(9B)R^(9C), —NHNR^(9B)R^(9C),—ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C), —NHC(O)NR^(9B)R^(9C),—N(O)_(m9), —NR^(9B)R^(9C), —C(O)R^(9D), —C(O)OR^(9D),—C(O)NR^(9B)R^(9C), —OR^(9A), —NR^(9B)SO₂R^(9A), —NR^(9B)C(O)R^(9D),—NR^(9B)C(O)OR^(9D), —NR^(9B)OR^(9D), —OCX^(9.1) ₃, —OCHX^(9.1) ₂,R³⁵-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), R³⁵-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4membered heteroalkyl), R³⁵-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R³⁵-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), R³⁵-substituted or unsubstituted aryl (e.g., C₆-C₁₀aryl, C₁₀ aryl, or phenyl), or R³⁵-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R⁹ is R³⁵-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁹ isR³⁵-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R⁹ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R⁹ is R³⁵-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R⁹ is R³⁵-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R⁹ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R⁹ is R³⁵-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R⁹ is R³⁵-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R⁹ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R⁹ is R³⁵-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R⁹ is R³⁵-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R⁹ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R⁹ is R³⁵-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁹ is R³⁵-substitutedaryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁹ is anunsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

In embodiments, R⁹ is R³⁵-substituted or unsubstituted heteroaryl (e.g.,5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R⁹ is R³⁵-substituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R⁹ is an unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹⁰ is halogen, —CX^(10.1) ₃, —CHX^(10.1) ₂,—CH₂X^(10.1), —CN, —N₃, —SO_(n10)R^(10A), —SO_(v10)NR^(10B)R^(10C),—NHNR^(10B)R^(10C), —ONR^(10B)R^(10C), —NHC(O)NHNR^(10B)R^(10C),—NHC(O)NR^(10B)R^(10C), —N(O)_(m10), —NR^(10B)R^(10C), —C(O)R^(10D),—C(O)OR^(10D), —C(O)NR^(10B)R^(10C), —OR^(10A), —NR^(10B)SO₂R^(10A),—NR^(10B)C(O)R^(10D), —NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D),—OCX^(10.1) ₃, —OCHX^(10.1) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. Inembodiments, R¹⁰ is hydrogen.

In embodiments, R¹⁰ is halogen, —CX^(10.1) ₃, —CHX^(10.1) ₂,—CH₂X^(10.1), —CN, —N₃, —SO_(n10)R^(10A), —SO_(v10)NR^(10B)R^(10C),—NHNR^(10B)R^(10C), —ONR^(10B)R^(10C), —NHC(O)NHNR^(10B)R^(10C),—NHC(O)NR^(10B)R^(10C), —N(O)_(m10), —NR^(10B)R^(10C), —C(O)R^(10D),—C(O)OR^(10D), —C(O)NR^(10B)R^(10C), —OR^(10A), —NR^(10B)SO₂R^(10A),—NR^(10B)C(O)R^(10D), —NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D),—OCX^(10.1) ₃, —OCHX^(10.1) ₂, R³⁸-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R³⁸-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R³⁸-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R³⁸-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³⁸-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR³⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹⁰ is R³⁸-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹⁰ isR³⁸-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R¹⁰ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R¹⁰ is R³⁸-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R¹⁰ is R³⁸-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R¹⁰ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R¹⁰ is R³⁸-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R¹⁰ is R³⁸-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R¹⁰ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R¹⁰ is R³⁸-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R¹⁰ is R³⁸-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R¹⁰ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R¹⁰ is R³⁸-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹⁰ isR³⁸-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R¹⁰ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R¹⁰ is R³⁸-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R¹⁰ is R³⁸-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R¹⁰ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, L⁷ is a bond, —O—, —S—, —NR^(7.2B)—, —C(O)—, —C(O)O—,—S(O)—, —S(O)₂—, substituted or unsubstituted alkylene (e.g., C₁-C₈alkylene, C₁-C₆ alkylene, or C₁-C₄ alkylene), substituted orunsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to6 membered heteroalkylene, or 2 to 4 membered heteroalkylene),substituted or unsubstituted cycloalkylene (e.g., C₃-C₈ cycloalkylene,C₃-C₆ cycloalkylene, or C₅-C₆ cycloalkylene), substituted orunsubstituted heterocycloalkylene (e.g., 3 to 8 memberedheterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6membered heterocycloalkylene), substituted or unsubstituted arylene(e.g., C₆-C₁₀ arylene, C₁₀ arylene, or phenylene), or substituted orunsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to9 membered heteroarylene, or 5 to 6 membered heteroarylene).

In embodiments, L⁷ is a bond, —O—, —S—, —NR^(7.2B)—, —C(O)—, —C(O)O—,—S(O)—, —S(O)₂—, R⁴¹-substituted or unsubstituted alkylene (e.g., C₁-C₈alkylene, C₁-C₆ alkylene, or C₁-C₄ alkylene), R⁴¹-substituted orunsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to6 membered heteroalkylene, or 2 to 4 membered heteroalkylene),R⁴¹-substituted or unsubstituted cycloalkylene (e.g., C₃-C₈cycloalkylene, C₃-C₆ cycloalkylene, or C₅-C₆ cycloalkylene),R⁴¹-substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5to 6 membered heterocycloalkylene), R⁴¹-substituted or unsubstitutedarylene (e.g., C₆-C₁₀ arylene, C₁₀ arylene, or phenylene), orR⁴¹-substituted or unsubstituted heteroarylene (e.g., 5 to 10 memberedheteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 memberedheteroarylene). In embodiments, L⁷ is a bond.

In embodiments, L⁷ is R⁴¹-substituted or unsubstituted alkylene (e.g.,C₁-C₈ alkylene, C₁-C₆ alkylene, or C₁-C₄ alkylene). In embodiments, L⁷is R⁴¹-substituted alkylene (e.g., C₁-C₈ alkylene, C₁-C₆ alkylene, orC₁-C₄ alkylene). In embodiments, L⁷ is an unsubstituted alkylene (e.g.,C₁-C₈ alkylene, C₁-C₆ alkylene, or C₁-C₄ alkylene).

In embodiments, L⁷ is R⁴¹-substituted or unsubstituted heteroalkylene(e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene,or 2 to 4 membered heteroalkylene). In embodiments, L⁷ isR⁴¹-substituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). Inembodiments, L⁷ is an unsubstituted heteroalkylene (e.g., 2 to 8membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4membered heteroalkylene).

In embodiments, L⁷ is R⁴¹-substituted or unsubstituted cycloalkylene(e.g., C₃-C₈ cycloalkylene, C₃-C₆ cycloalkylene, or C₅-C₆cycloalkylene). In embodiments, L⁷ is R⁴¹-substituted cycloalkylene(e.g., C₃-C₈ cycloalkylene, C₃-C₆ cycloalkylene, or C₅-C₆cycloalkylene). In embodiments, L⁷ is an unsubstituted cycloalkylene(e.g., C₃-C₈ cycloalkylene, C₃-C₆ cycloalkylene, or C₅-C₆cycloalkylene).

In embodiments, L⁷ is R⁴¹-substituted or unsubstitutedheterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene).In embodiments, L⁷ is R⁴¹-substituted heterocycloalkylene (e.g., 3 to 8membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5to 6 membered heterocycloalkylene). In embodiments, L⁷ is anunsubstituted heterocycloalkylene (e.g., 3 to 8 memberedheterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6membered heterocycloalkylene).

In embodiments, L⁷ is R⁴¹-substituted or unsubstituted arylene (e.g.,C₆-C₁₀ arylene, C₁₀ arylene, or phenylene). In embodiments, L⁷ isR⁴¹-substituted arylene (e.g., C₆-C₁₀ arylene, C₁₀ arylene, orphenylene). In embodiments, L⁷ is an unsubstituted arylene (e.g., C₆-C₁₀arylene, C₁₀ arylene, or phenylene).

In embodiments, L⁷ is R⁴¹-substituted or unsubstituted heteroarylene(e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or5 to 6 membered heteroarylene). In embodiments, L⁷ is R⁴¹-substitutedheteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 memberedheteroarylene, or 5 to 6 membered heteroarylene). In embodiments, L⁷ isan unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5to 9 membered heteroarylene, or 5 to 6 membered heteroarylene).

In embodiments, R^(1A) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(11A)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(11A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(11A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(11A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(11A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(11A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(2A) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(14A)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(14A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(14A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(14A)-substituted orunsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(14A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(14A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(3A) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(17A)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(17A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(17A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(17A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(17A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(17A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(3.2A) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(17.2A)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(17.2A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(17.2A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(17.2A)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(17.2A)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(17.2A)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(33A) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(17.3A)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(17.3A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(17.3A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(17.3A)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(17.3A)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(17.3A)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(4A) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(20A)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(20A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(20A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(20A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(20A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(20A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(5A) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(23A)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(23A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(23A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(23A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(23A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(23A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(6A) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(26A)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(7A) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(29A)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(29A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(29A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(29A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(29A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(29A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(8A) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(32A)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(32A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(32A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(32A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(32A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(32A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(9A) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(35A)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(35A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(35A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(35A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(35A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(35A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(10A) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(38A)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(38A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(38A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(38A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(38A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(38A)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(1B) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(11B)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(11B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(11B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(11B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(11B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(11B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R^(1B) and R^(1C) substituentsbonded to the same nitrogen atom may optionally be joined to form aR^(11B)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or R^(11B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(2B) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(14B)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(14B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(14B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(14B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(14B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(14B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R^(2B) and R^(2C) substituentsbonded to the same nitrogen atom may optionally be joined to form aR^(14B)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or R^(14B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(3B) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(17B)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(17B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(17B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(17B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(17B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(17B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R^(3B) and R^(3C) substituentsbonded to the same nitrogen atom may optionally be joined to form aR^(17B)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or R^(17B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(3.2B) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(17.2B)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(17.2B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(17.2B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(17.2B)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(17.2B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(17.2B)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(33B) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(17.3B)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(17.3B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(17.3B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(17.3B)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(17.3B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(17.3B)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(4B) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(20B)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(20B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(20B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(20B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(20B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(20B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R^(4B) and R^(4C) substituentsbonded to the same nitrogen atom may optionally be joined to form aR^(20B)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or R^(20B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(5B) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(23B)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(23B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(23B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(23B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(23B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(23B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R^(5B) and R^(5C) substituentsbonded to the same nitrogen atom may optionally be joined to form aR^(23B)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or R^(23B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(6B) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(26B)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R^(6B) and R^(6C) substituentsbonded to the same nitrogen atom may optionally be joined to form aR^(26B)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or R^(26B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(7B) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(29B)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(29B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(29B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(29B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(29B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(29B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R^(7B) and R^(7C) substituentsbonded to the same nitrogen atom may optionally be joined to form aR^(29B)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or R^(29B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(8B) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(32B)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(32B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(32B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(32B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(32B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(32B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R^(8B) and R^(8C) substituentsbonded to the same nitrogen atom may optionally be joined to form aR^(32B)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or R^(32B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(9B) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(35B)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(35B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(35B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(35B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(35B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(35B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R^(9B) and R^(9C) substituentsbonded to the same nitrogen atom may optionally be joined to form aR^(35B)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or R^(35B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(10B) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(38B)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(38B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(38B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(38B)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(38B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(38B)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R^(10B) and R^(10C) substituentsbonded to the same nitrogen atom may optionally be joined to form aR^(38B)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or R^(38B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(1C) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(11C)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(11C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(11C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(11C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(11C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(11C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R^(1B) and R^(1C) substituentsbonded to the same nitrogen atom may optionally be joined to form aR^(11C)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or R^(11C)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(2C) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(14C)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(14C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(14C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(14C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(14C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(14C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R^(2B) and R^(2C) substituentsbonded to the same nitrogen atom may optionally be joined to form aR^(14C)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or R^(14C)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(3C) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(17C)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(17C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(17C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(17C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(17C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(17C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R^(3B) and R^(3C) substituentsbonded to the same nitrogen atom may optionally be joined to form aR^(17C)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or R^(17C)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(3.2C) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(17.2C)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(17.2C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(17.2C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(17.2C)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(17.2C)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(17.2C)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(33C) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(17.3C)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(17.3C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(17.3C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(17.3C)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(17.3C)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(17.3C)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(4C) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(20C)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(20C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(20C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(20C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(20C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(20C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R^(4B) and R^(4C) substituentsbonded to the same nitrogen atom may optionally be joined to form aR^(20C)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or R^(20C)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(5C) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(23C)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(23C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(23C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(23C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(23C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(23C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R^(5B) and R^(5C) substituentsbonded to the same nitrogen atom may optionally be joined to form aR^(23C)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or R^(23C)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(6C) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(26C)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R^(6B) and R^(6C) substituentsbonded to the same nitrogen atom may optionally be joined to form aR^(26C)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or R^(26C)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(7C) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(29C)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(29C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(29C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(29C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(29C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(29C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R^(7B) and R^(7C) substituentsbonded to the same nitrogen atom may optionally be joined to form aR^(29C)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or R^(29C)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(8C) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(32C)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(32C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(32C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(32C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(32C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(32C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R^(8B) and R^(8C) substituentsbonded to the same nitrogen atom may optionally be joined to form aR^(32C)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or R^(32C)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(9C) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(35C)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(35C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(35C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(35C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(35C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(35C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R^(9B) and R^(9C) substituentsbonded to the same nitrogen atom may optionally be joined to form aR^(35C)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or R^(35C)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(10C) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(38C)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(38C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(38C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(38C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(38C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(38C)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R^(10B) and R^(10C) substituentsbonded to the same nitrogen atom may optionally be joined to form aR^(38B)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or R^(38B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(1D) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(11D)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(11D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(11D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(11D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(11D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(11D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(2D) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(14D)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(14D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(14D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(14D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(14D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(14D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(3D) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(17D)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(17D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(17D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(17D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(17D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(17D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(3.2D) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(17.2D)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(17.2D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(17.2D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(17.2D)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(17.2D)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(17.2D)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(33D) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(17.3D)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(17.3D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(17.3D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(17.3D)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(17.3D)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(17.3D)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(4D) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(20D)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(20D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(20D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(20D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(20D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(20D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(5D) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(23D)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(23D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(23D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(23D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(23D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(23D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(6D) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(26D)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(7D) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(29D)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(29D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(29D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(29D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(29D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(29D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R^(7D) is hydrogen. Inembodiments, R^(7D) is —NH₂. In embodiments, R^(7D) is —CH₃. Inembodiments, R^(7D) is unsubstituted C₁-C₃ alkyl.

In embodiments, R^(8D) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(32D)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(32D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(32D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(32D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(32D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(32D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(9D) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(35D)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(35D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(35D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(35D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(35D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(35D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(10D) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(38D)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(38D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(38D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(38D)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(38D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(38D)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(7.2B) is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, R^(41.2B)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(41.2B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(41.2B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(41.2B)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(41.2B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(41.2B)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R¹¹ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂, R¹²-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R¹²-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R¹²-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R¹²-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R¹²-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R¹²-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R¹¹ is R¹²-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹¹ isR¹²-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R¹¹ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R¹¹ is R¹²-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R¹¹ is R¹²-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R¹¹ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R¹¹ is R¹²-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R¹¹ is R¹²-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R¹¹ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R¹¹ is R¹²-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R¹¹ is R¹²-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R¹¹ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R¹¹ is R¹²-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹¹ isR¹²-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R¹¹ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R¹¹ is R¹²-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R¹¹ is R¹²-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R¹¹ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R¹² is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂, R¹³-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R¹³-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R¹³-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R¹³-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R¹³-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R¹³-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R¹² is R¹³-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹² isR¹³-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R¹² is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R¹² is R¹³-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R¹² is R¹³-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R¹² is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R¹² is R¹³-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R¹² is R¹³-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R¹² is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R¹² is R¹³-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R¹² is R¹³-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R¹² is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R¹² is R¹³-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹² isR¹³-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R¹² is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R¹² is R¹³-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R¹² is R¹³-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R¹² is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R¹⁴ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂, R¹⁵-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R¹⁵-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R¹⁵-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R¹⁵-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R¹⁵-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R¹⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R¹⁴ is R¹⁵-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹⁴ isR¹⁵-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R¹⁴ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R¹⁴ is R¹⁵-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R¹⁴ is R¹⁵-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R¹⁴ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R¹⁴ is R¹⁵-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R¹⁴ is R¹⁵-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R¹⁴ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R¹⁴ is R¹⁵-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R¹⁴ is R¹⁵-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R¹⁴ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R¹⁴ is R¹⁵-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹⁴ isR¹⁵-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R¹⁴ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R¹⁴ is R¹⁵-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R¹⁴ is R¹⁵-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R¹⁴ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R¹⁵ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂, R¹⁶-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R¹⁶-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R¹⁶-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R¹⁶-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R¹⁶-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R¹⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R¹⁵ is R¹⁶-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹⁵ isR¹⁶-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R¹⁵ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R¹⁵ is R¹⁶-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R¹⁵ is R¹⁶-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R¹⁵ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R¹⁵ is R¹⁶-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R¹⁵ is R¹⁶-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R¹⁵ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R¹⁵ is R¹⁶-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R¹⁵ is R¹⁶-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R¹⁵ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R¹⁵ is R¹⁶-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹⁵ isR¹⁶-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R¹⁵ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R¹⁵ is R¹⁶-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R¹⁵ is R¹⁶-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R¹⁵ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R¹⁷ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂, R¹⁸-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R¹⁸-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R¹⁸-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R¹⁸-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R¹⁸-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R¹⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R¹⁷ is R¹⁸-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹⁷ isR¹⁸-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R¹⁷ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R¹⁷ is R¹⁸-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R¹⁷ is R¹⁸-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R¹⁷ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R¹⁷ is R¹⁸-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R¹⁷ is R¹⁸-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R¹⁷ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R¹⁷ is R¹⁸-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R¹⁷ is R¹⁸-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R¹⁷ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R¹⁷ is R¹⁸-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹⁷ isR¹⁸-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R¹⁷ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R¹⁷ is R¹⁸-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R¹⁷ is R¹⁸-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R¹⁷ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R¹⁸ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂, R¹⁹-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R¹⁹-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R¹⁹-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R¹⁹-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R¹⁹-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R¹⁹-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R¹⁸ is R¹⁹-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹⁸ isR¹⁹-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R¹⁸ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R¹⁸ is R¹⁹-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R¹⁸ is R¹⁹-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R¹⁸ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R¹⁸ is R¹⁹-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R¹⁸ is R¹⁹-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R¹⁸ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R¹⁸ is R¹⁹-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R¹⁸ is R¹⁹-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R¹⁸ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R¹⁸ is R¹⁹-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹⁸ isR¹⁹-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R¹⁸ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R¹⁸ is R¹⁹-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R¹⁸ is R¹⁹-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R¹⁸ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(17.2) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂,R^(18.2)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(18.2)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R^(18.2)-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), R^(18.2)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(18.2)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(18.2)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(17.2) is R^(18.2)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R^(17.2) is R^(18.2)-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl). In embodiments, R^(17.2) is an unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

In embodiments, R^(17.2) is R^(18.2)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R^(17.2)is R^(18.2)-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl,2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). Inembodiments, R^(17.2) is an unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl).

In embodiments, R^(17.2) is R^(18.2)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl). In embodiments, R^(17.2) is R^(18.2)-substituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R^(17.2) is an unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

In embodiments, R^(17.2) is R^(18.2)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, R^(17.2) is R^(18.2)-substituted heterocycloalkyl (e.g., 3to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl). In embodiments, R^(17.2) is anunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R^(17.2) is R^(18.2)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R^(17.2) isR^(18.2)-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R^(17.2) is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl, or phenyl).

In embodiments, R^(17.2) is R^(18.2)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R^(17.2) isR^(18.2)-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments,R^(17.2) is an unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(18.2) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂,R^(19.2)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(19.2)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R^(19.2)-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), R^(19.2)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(19.2)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(19.2)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(18.2) is R^(19.2)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R^(18.2) is R^(19.2)-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl). In embodiments, R^(18.2) is an unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

In embodiments, R^(18.2) is R^(19.2)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R^(18.2)is R^(19.2)-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl,2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). Inembodiments, R^(18.2) is an unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl).

In embodiments, R^(18.2) is R^(19.2)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl). In embodiments, R^(18.2) is R^(19.2)-substituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R^(18.2) is an unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

In embodiments, R^(18.2) is R^(19.2)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, R^(18.2) is R^(19.2)-substituted heterocycloalkyl (e.g., 3to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl). In embodiments, R^(18.2) is anunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R^(18.2) is R^(19.2)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R^(18.2) isR^(19.2)-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R^(18.2) is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl, or phenyl).

In embodiments, R^(18.2) is R^(19.2)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R^(18.2) isR^(19.2)-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments,R^(18.2) is an unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(17.3) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂,R^(18.3)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(18.3)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R^(18.3)-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), R^(18.3)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(18.3)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(18.3)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(17.3) is R^(18.3)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R^(17.3) is R^(18.3)-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl). In embodiments, R^(17.3) is an unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

In embodiments, R^(17.3) is R^(18.3)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R^(17.3)is R^(18.3)-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl,2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). Inembodiments, R^(17.3) is an unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl).

In embodiments, R^(17.3) is R^(18.3)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl). In embodiments, R^(17.3) is R^(18.3)-substituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R^(17.3) is an unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

In embodiments, R^(17.3) is R^(18.3)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, R^(17.3) is R^(18.3)-substituted heterocycloalkyl (e.g., 3to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl). In embodiments, R^(17.3) is anunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R^(17.3) is R^(18.3)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R^(17.3) isR^(18.3)-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R^(17.3) is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl, or phenyl).

In embodiments, R^(17.3) is R^(18.3)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R^(17.3) isR^(18.3)-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments,R^(17.3) is an unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(18.3) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂,R^(19.3)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(19.3)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R^(19.3)-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), R^(19.3)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(19.3)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(19.3)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R^(18.3) is R^(19.3)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R^(18.3) is R^(19.3)-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl). In embodiments, R^(18.3) is an unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

In embodiments, R^(18.3) is R^(19.3)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R^(18.3)is R^(19.3)-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl,2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). Inembodiments, R^(18.3) is an unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl).

In embodiments, R^(18.3) is R^(19.3)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl). In embodiments, R^(18.3) is R^(19.3)-substituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R^(18.3) is an unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

In embodiments, R^(18.3) is R^(19.3)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, R^(18.3) is R^(19.3)-substituted heterocycloalkyl (e.g., 3to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl). In embodiments, R^(18.3) is anunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R^(18.3) is R^(19.3)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R^(18.3) isR^(19.3)-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R^(18.3) is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl, or phenyl).

In embodiments, R^(18.3) is R^(19.3)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R^(18.3) isR^(19.3)-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments,R^(18.3) is an unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R²⁰ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂, R²¹-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R²¹-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R²¹-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R²¹-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R²¹-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R²¹-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R²⁰ is R²¹-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R²⁰ isR²¹-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R²⁰ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R²⁰ is R²¹-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R²⁰ is R²¹-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R²⁰ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R²⁰ is R²¹-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R²⁰ is R²¹-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R²⁰ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R²⁰ is R²¹-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R²⁰ is R²¹-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R²⁰ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R²⁰ is R²¹-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R²⁰ isR²¹-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R²⁰ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R²⁰ is R²¹-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R²⁰ is R²¹-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R²⁰ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R²¹ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂, R²²-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R²²-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R²²-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R²²-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R²²-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R²²-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R²¹ is R²²-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R²¹ isR²²-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R²¹ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R²¹ is R²²-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R²¹ is R²²-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R²¹ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R²¹ is R²²-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R²¹ is R²²-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R²¹ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R²¹ is R²²-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R²¹ is R²²-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R²¹ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R²¹ is R²²-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R²¹ isR²²-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R²¹ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R²¹ is R²²-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R²¹ is R²²-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R²¹ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R²³ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂, R²⁴-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R²⁴-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R²⁴-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R²⁴-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R²⁴-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R²⁴-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R²³ is R²⁴-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R²³ isR²⁴-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R²³ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R²³ is R²⁴-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R²³ is R²⁴-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R²³ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R²³ is R²⁴-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R²³ is R²⁴-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R²³ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R²³ is R²⁴-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R²³ is R²⁴-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R²³ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R²³ is R²⁴-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R²³ isR²⁴-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R²³ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R²³ is R²⁴-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R²³ is R²⁴-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R²³ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R²⁴ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂, R²⁵-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R²⁵-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R²⁵-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R²⁵-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R²⁵-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R²⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R²⁴ is R²⁵-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R²⁴ isR²⁵-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R²⁴ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R²⁴ is R²⁵-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R²⁴ is R²⁵-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R²⁴ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R²⁴ is R²⁵-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R²⁴ is R²⁵-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R²⁴ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R²⁴ is R²⁵-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R²⁴ is R²⁵-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R²⁴ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R²⁴ is R²⁵-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R²⁴ isR²⁵-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R²⁴ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R²⁴ is R²⁵-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R²⁴ is R²⁵-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R²⁴ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R²⁶ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂, R²⁷-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R²⁷-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R²⁷-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R²⁷-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R²⁷-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R²⁷-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R²⁶ is R²⁷-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R²⁶ isR²⁷-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R²⁶ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R²⁶ is R²⁷-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R²⁶ is R²⁷-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R²⁶ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R²⁶ is R²⁷-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R²⁶ is R²⁷-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R²⁶ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R²⁶ is R²⁷-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R²⁶ is R²⁷-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R²⁶ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R²⁶ is R²⁷-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R²⁶ isR²⁷-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R²⁶ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R²⁶ is R²⁷-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R²⁶ is R²⁷-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R²⁶ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R²⁷ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂, R²⁸-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R²⁸-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R²⁸-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R²⁸-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R²⁸-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R²⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R²⁷ is R²⁸-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R²⁷ isR²⁸-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R²⁷ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R²⁷ is R²⁸-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R²⁷ is R²⁸-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R²⁷ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R²⁷ is R²⁸-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R²⁷ is R²⁸-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R²⁷ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R²⁷ is R²⁸-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R²⁷ is R²⁸-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R²⁷ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R²⁷ is R²⁸-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R²⁷ isR²⁸-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R²⁷ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R²⁷ is R²⁸-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R²⁷ is R²⁸-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R²⁷ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R²⁹ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂, R³⁰-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R³⁰-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R³⁰-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁰-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R³⁰-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R³⁰-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, R²⁹ is oxo. In embodiments, R²⁹ is —CH₃. Inembodiments, R²⁹ is —COOH. In embodiments, R²⁹ is —NHC(O)NH₂. Inembodiments, R²⁹ is —OH. In embodiments, R²⁹ is —NH₂. In embodiments,R²⁹ is —CONH₂. In embodiments, R²⁹ is —NHC(O)OH. In embodiments, R²⁹ is—SO₂CH₃. In embodiments, R²⁹ is —NHSO₂CH₃. In embodiments, R²⁹ is—SO₂CH₂CH₃. In embodiments, R²⁹ is —SO₂R³⁰. In embodiments, R²⁹ is—SO₂CH(CH₃)₂.

In embodiments, R²⁹ is R³⁰-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R²⁹ isR³⁰-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R²⁹ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R²⁹ is R³⁰-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R²⁹ is R³⁰-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R²⁹ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R²⁹ is R³⁰-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R²⁹ is R³⁰-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R²⁹ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R²⁹ is R³⁰-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R²⁹ is R³⁰-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R²⁹ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R²⁹ is R³⁰-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R²⁹ isR³⁰-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R²⁹ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R²⁹ is R³⁰-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R²⁹ is R³⁰-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R²⁹ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R³⁰ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂, R³¹-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R³¹-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R³¹-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R³¹-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R³¹-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R³¹-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R³⁰ is R³¹-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R³⁰ isR³¹-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R³⁰ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R³⁰ is R³¹-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R³⁰ is R³¹-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R³⁰ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R³⁰ is R³¹-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R³⁰ is R³¹-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R³⁰ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R³⁰ is R³¹-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R³⁰ is R³¹-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R³⁰ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R³⁰ is R³¹-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R³⁰ isR³¹-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R³⁰ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R³⁰ is R³¹-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R³⁰ is R³¹-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R³⁰ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R³² is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂, R³³-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R³³-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R³³-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R³³-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R³³-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R³³-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R³² is R³³-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R³² isR³³-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R³² is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R³² is R³³-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R³² is R³³-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R³² is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R³² is R³³-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R³² is R³³-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R³² is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R³² is R³³-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R³² is R³³-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R³² is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R³² is R³³-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R³² isR³³-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R³² is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R³² is R³³-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R³² is R³³-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R³² is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R³³ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂, R³⁴-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C 4alkyl), R³⁴-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R³⁴-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁴-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R³⁴-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R³⁴-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R³³ is R³⁴-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R³³ isR³⁴-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R³³ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R³³ is R³⁴-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R³³ is R³⁴-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R³³ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R³³ is R³⁴-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R³³ is R³⁴-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R³³ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R³³ is R³⁴-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R³³ is R³⁴-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R³³ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R³³ is R³⁴-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R³³ isR³⁴-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R³³ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R³³ is R³⁴-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R³³ is R³⁴-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R³³ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R³⁵ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂, R³⁶-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R³⁶-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R³⁶-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁶-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R³⁶-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R³⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R³⁵ is R³⁶-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R³⁵ isR³⁶-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R³⁵ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R³⁵ is R³⁶-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R³⁵ is R³⁶-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R³⁵ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R³⁵ is R³⁶-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R³⁵ is R³⁶-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R³⁵ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R³⁵ is R³⁶-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R³⁵ is R³⁶-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R³⁵ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R³⁵ is R³⁶-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R³⁵ isR³⁶-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R³⁵ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R³⁵ is R³⁶-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R³⁵ is R³⁶-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R³⁵ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R³⁶ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)0H, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂, R³⁷-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R³⁷-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R³⁷-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁷-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R³⁷-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R³⁷-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R³⁶ is R³⁷-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R³⁶ isR³⁷-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R³⁶ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R³⁶ is R³⁷-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R³⁶ is R³⁷-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R³⁶ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R³⁶ is R³⁷-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R³⁶ is R³⁷-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R³⁶ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R³⁶ is R³⁷-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R³⁶ is R³⁷-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R³⁶ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R³⁶ is R³⁷-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R³⁶ isR³⁷-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R³⁶ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R³⁶ is R³⁷-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R³⁶ is R³⁷-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R³⁶ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R³⁸ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂, R³⁹-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R³⁹-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R³⁹-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁹-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R³⁹-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R³⁹-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R³⁸ is R³⁹-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R³⁸ isR³⁹-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R³⁸ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R³⁸ is R³⁹-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R³⁸ is R³⁹-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R³⁸ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R³⁸ is R³⁹-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R³⁸ is R³⁹-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R³⁸ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R³⁸ is R³⁹-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R³⁸ is R³⁹-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R³⁸ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R³⁸ is R³⁹-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R³⁸ isR³⁹-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R³⁸ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R³⁸ is R³⁹-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R³⁸ is R³⁹-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R³⁸ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R³⁹ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂, R⁴⁰-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C i-C 4alkyl), R⁴⁰-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁴⁰-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴⁰-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁴⁰-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R⁴⁰-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R³⁹ is R⁴⁰-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R³⁹ isR⁴⁰-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R³⁹ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R³⁹ is R⁴⁰-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R³⁹ is R⁴⁰-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R³⁹ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R³⁹ is R⁴⁰-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R³⁹ is R⁴⁰-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R³⁹ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R³⁹ is R⁴⁰-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R³⁹ is R⁴⁰-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R³⁹ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R³⁹ is R⁴⁰-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R³⁹ isR⁴⁰-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R³⁹ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R³⁹ is R⁴⁰-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R³⁹ is R⁴⁰-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R³⁹ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁴¹ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂, R⁴²-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁴²-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁴²-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴²-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁴²-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R⁴²-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R⁴¹ is R⁴²-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁴¹ isR⁴²-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R⁴¹ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R⁴¹ is R⁴²-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R⁴¹ is R⁴²-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R⁴¹ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R⁴¹ is R⁴²-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R⁴¹ is R⁴²-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R⁴¹ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R⁴¹ is R⁴²-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R⁴¹ is R⁴²-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R⁴¹ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R⁴¹ is R⁴²-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁴¹-R⁴²-substitutedaryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁴¹ is anunsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

In embodiments, R⁴¹ is R⁴²-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R⁴¹ is R⁴²-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R⁴¹ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁴² is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)0H, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂, R⁴³-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁴³-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁴³-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴³-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁴³-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R⁴³-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R⁴² is R⁴³-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁴² isR⁴³-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R⁴² is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R⁴² is R⁴³-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R⁴² is R⁴³-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R⁴² is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R⁴² is R⁴³-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R⁴² is R⁴³-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R⁴² is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R⁴² is R⁴³-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R⁴² is R⁴³-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R⁴² is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R⁴² is R⁴³-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁴² isR⁴³-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R⁴² is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R⁴² is R⁴³-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R⁴² is R⁴³-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R⁴² is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(41.2B) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂,R^(42.2B)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(42.2B)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R^(42.2B)-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), R^(42.2B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(42.2B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl, or phenyl), or R^(42.2B)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl).

In embodiments, R^(41.2B) is R^(42.2B)-substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R^(41.2B) is R^(42.2B)-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). In embodiments, R^(41.2B) is an unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

In embodiments, R ^(41.2B) is R_(42.2B)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R^(41.2B)is R^(42.2B)-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl,2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). Inembodiments, R^(41 2B) is an unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl).

In embodiments, R^(41.2B) is R^(42.2B)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl). In embodiments, R^(41.2B) is R^(42.2B)-substitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl). In embodiments, R^(41.2B) is an unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

In embodiments, R ^(41.2B) is R^(42.2B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, R^(41.2B) is R^(42.2B)-substituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl). In embodiments, R^(41 2B) is anunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R^(41.2B) is R^(42.2B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R^(41.2B) isR^(42.2B)-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R^(41.2B) is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl, or phenyl).

In embodiments, R ^(41.2B) is R^(42.2B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R^(41.2B) isR^(42.2B)-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). Inembodiments, R^(41.2B) is an unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

R^(42.2B) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂, —OCHI₂, —OCHF₂,R^(43.2B)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), R^(43.2B)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R^(43.2B)-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), R^(43.2B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(43.2B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl, or phenyl), or R^(43.2B)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl).

In embodiments, R^(42.2B) is R^(43.2B)-substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R^(42.2B) is R^(43.2B)-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). In embodiments, R^(42.2B) is an unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

In embodiments, R^(42.2B) is R^(43.2B)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R^(42.2B)is R^(43.2B)-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl,2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). Inembodiments, R^(42.2B) is an unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl).

In embodiments, R^(42.2B) is R^(43.2B)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl). In embodiments, R^(42.2B) is R^(43.2B)-substitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl). In embodiments, R^(42.2B) is an unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

In embodiments, R^(42.2B) is R^(43.2B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, R^(42.2B) is R^(43.2B)-substituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl). In embodiments, R^(42.2B) is anunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R^(42.2B) is R^(43.2B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R^(42.2B) isR^(43.2B)-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R^(42.2B) is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl, or phenyl).

In embodiments, R^(42.2B) is R^(43.2B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R^(42.2B) isR^(43.2B)-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). Inembodiments, R^(42.2B) is an unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

R¹³, R¹⁶, R¹⁹, R^(19.2), R^(19.3), R²², R²⁵, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰,R⁴³, and R^(43.2B) are independently hydrogen, oxo, halogen, —CCl₃,—CBr₃, —CF₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCH—Br₂, —OCHI₂, —OCHF₂, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

R^(11A), R^(11B), R^(11C), R^(11D), R^(14A), R^(14B), R^(14C), R^(14D),R^(17A), R^(17B), R^(17C), R^(17D), R^(17.2A), R^(17.2B), R^(17.2C),R^(17.2D), R^(17.3A), R^(17.3B), R^(17.3C), R^(17.3D), R^(20A), R^(20B),R^(20C), R^(20D), R^(23A), R^(23B), R^(23C), R^(23D), R^(26A), R^(26B),R^(26C), R^(26D), R^(29A), R^(29B), R^(29C), R^(29D), R^(32A), R^(32B),R^(32C), R^(32D), R^(35A), R^(35B), R^(35C), R^(35D), R^(38A), R^(38B),R^(38C), and R^(38D) are independently hydrogen, oxo, halogen, —CCl₃,—CBr₃, —CF₃, —CI₃, —CN, —OH, —NH₂, —COOH, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCH—Br₂,—OCHI₂, —OCHF₂, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, X^(1.1) is —Cl. In embodiments, X^(1.1) is —F. Inembodiments, X^(1.1) is —Br. In embodiments, X^(1.1) is —I. Inembodiments, X^(2.1) is —Cl. In embodiments, X^(2.1) is —F. Inembodiments, X^(2.1) is —Br. In embodiments, X^(2.1) is —I. Inembodiments, X^(3.1) is —Cl. In embodiments, X^(3.1) is —F. Inembodiments, X^(3.1) is —Br. In embodiments, X^(3.1) is —I. Inembodiments, X^(3.2) is —Cl. In embodiments, X^(3.2) is —F. Inembodiments, X^(3.2) is —Br. In embodiments, X^(3.2) is —I. Inembodiments, X^(3.3) is —Cl. In embodiments, X^(3.3) is —F. Inembodiments, X^(3.3) is —Br. In embodiments, X^(3.3) is —I. Inembodiments, X^(4.1) is —Cl. In embodiments, X^(4.1) is —F. Inembodiments, X^(4.1) is —Br. In embodiments, X^(4.1) is –I. Inembodiments, X^(5.1) is —Cl. In embodiments, X^(5.1) is —F. Inembodiments, X^(5.1) is —Br. In embodiments, X^(5.1) is —I. Inembodiments, X^(6.1) is —Cl. In embodiments, X^(6.1) is —F. Inembodiments, X^(6.1) is —Br. In embodiments, X^(6.1) is —I. Inembodiments, X^(7.1) is —Cl. In embodiments, X^(7.1) is —F. Inembodiments, X^(7.1) is —Br. In embodiments, X^(7.1) is —I. Inembodiments, X^(8.1) is —Cl. In embodiments, X^(8.1) is —F. Inembodiments, X^(8.1) is —Br. In embodiments, X^(8.1) is —I. Inembodiments, X^(9.1) is —Cl. In embodiments, X^(9.1) is —F. Inembodiments, X^(9.1) is —Br. In embodiments, X^(9.1) is —I. Inembodiments, X^(10.1) is —Cl. In embodiments, X^(10.1) is —F. Inembodiments, X^(10.1) is —Br. In embodiments, X^(10.1) is —I.

In embodiments, X^(1.1) is —Cl, and X^(1.1) is N. In embodiments,X^(1.1) is —F, and X^(1.1) is N. In embodiments, X^(1.1) is —Br, andX^(1.1) is N. In embodiments, X^(1.1) is —I, and X¹ is N. Inembodiments, X^(2.1) is —Cl, and X¹ is N. In embodiments, X^(2.1) is —F,and X¹ is N. In embodiments, X^(2.1) is —Br, and X¹ is N. Inembodiments, X^(2.1) is —I, and X¹ is N. In embodiments, X^(3.1) is —Cl,and X¹ is N. In embodiments, X^(3.1) is —F, and X¹ is N. In embodiments,X^(3.1) is —Br, and X¹ is N. In embodiments, X^(3.1) is —I, and X¹ is N.In embodiments, X^(4.1) is —Cl, and X¹ is N. In embodiments, X^(4.1) is—F, and X¹ is N. In embodiments, X^(4.1) is —Br, and X¹ is N. Inembodiments, X^(4.1) is —I, and X¹ is N. In embodiments, X^(5.1) is —Cl,and X¹ is N. In embodiments, X^(5.1) is —F, and X¹ is N. In embodiments,X^(5.1) is —Br, and X¹ is N. In embodiments, X^(5.1) is —I, and X¹ is N.In embodiments, X^(6.1) is —Cl, and X¹ is N. In embodiments, X^(6.1) is—F, and X¹ is N. In embodiments, X^(6.1) is —Br, and X¹ is N. Inembodiments, X^(6.1) is —I, and X¹ is N. In embodiments, X^(7.1) is —Cl,and X¹ is N. In embodiments, X^(7.1) is —F, and X¹ is N. In embodiments,X^(7.1) is —Br, and X¹ is N. In embodiments, X^(7.1) is —I, and X¹ is N.In embodiments, X^(8.1) is —Cl, and X¹ is N. In embodiments, X^(8.1) is—F, and X¹ is N. In embodiments, X^(8.1) is —Br, and X¹ is N. Inembodiments, X^(8.1) is —I, and X¹ is N. In embodiments, X^(9.1) is —Cl,and X¹ is N. In embodiments, X^(9.1) is —F, and X¹ is N. In embodiments,X^(9.1) is —Br, and X¹ is N. In embodiments, X^(9.1) is —I, and X¹ is N.In embodiments, X^(10.1) is —Cl, and X¹ is N. In embodiments, X^(10.1)is —F, and X¹ is N. In embodiments, X^(10.1) is —Br, and X¹ is N. Inembodiments, X^(10.1) is —I, and X¹ is N.

In embodiments, X^(1.1) is —Cl, and X² is N. In embodiments, X^(1.1) is—F, and X² is N. In embodiments, X^(1.1) is —Br, and X² is N. Inembodiments, X^(1.1) is —I, and X² is N. In embodiments, X^(2.1) is —Cl,and X² is N. In embodiments, X^(2.1) is —F, and X² is N. In embodiments,X^(2.1) is —Br, and X² is N. In embodiments, X^(2.1) is —I, and X² is N.In embodiments, X^(3.1) is —Cl, and X² is N. In embodiments, X^(3.1) is—F, and X² is N. In embodiments, X^(3.1) is —Br, and X² is N. Inembodiments, X^(3.1) is —I, and X² is N. In embodiments, X^(4.1) is —Cl,and X² is N. In embodiments, X^(4.1) is —F, and X² is N. In embodiments,X^(4.1) is —Br, and X² is N. In embodiments, X^(4.1) is —I, and X² is N.In embodiments, X^(5.1) is —Cl, and X² is N. In embodiments, X^(5.1) is—F, and X² is N. In embodiments, X^(5.1) is —Br, and X² is N. Inembodiments, X^(5.1) is —I, and X² is N. In embodiments, X^(6.1) is —Cl,and X² is N. In embodiments, X^(6.1) is —F, and X² is N. In embodiments,X^(6.1) is —Br, and X² is N. In embodiments, X^(6.1) is —I, and X² is N.In embodiments, X^(7.1) is —Cl, and X² is N. In embodiments, X^(7.1) is—F, and X² is N. In embodiments, X^(7.1) is —Br, and X² is N. Inembodiments, X^(7.1) is —I, and X² is N. In embodiments, X^(8.1) is —Cl,and X² is N. In embodiments, X^(8.1) is —F, and X² is N. In embodiments,X^(8.1) is —Br, and X² is N. In embodiments, X^(8.1) is —I, and X² is N.In embodiments, X^(9.1) is —Cl, and X² is N. In embodiments, X^(9.1) is—F, and X² is N. In embodiments, X^(9.1) is —Br, and X² is N. Inembodiments, X^(9.1) is —I, and X² is N. In embodiments, X^(10.1) is—Cl, and X² is N. In embodiments, X^(10.1) is —F, and X² is N. Inembodiments, X^(10.1) is —Br, and X² is N. In embodiments, X^(10.1) is—I, and X² is N.

In embodiments, X^(1.1) is —Cl, and X³ is N. In embodiments, X^(1.1) is—F, and X³ is N. In embodiments, X^(1.1) is —Br, and X³ is N. Inembodiments, X^(1.1) is —I, and X³ is N. In embodiments, X^(2.1) is —Cl,and X³ is N. In embodiments, X^(2.1) is —F, and X³ is N. In embodiments,X^(2.1) is —Br, and X³ is N. In embodiments, X^(2.1) is —I, and X³ is N.In embodiments, X³⁻¹ is —Cl, and X³ is N. In embodiments, X^(3.1) is —F,and X³ is N. In embodiments, X^(3.1) is —Br, and X³ is N. Inembodiments, X^(3.1) is —I, and X³ is N. In embodiments, X^(4.1) is —Cl,and X³ is N. In embodiments, X^(4.1) is —F, and X³ is N. In embodiments,X^(4.1) is —Br, and X³ is N. In embodiments, X^(4.1) is —I, and X³ is N.In embodiments, X^(5.1) is —Cl, and X³ is N. In embodiments, X^(5.1) is—F, and X³ is N. In embodiments, X^(5.1) is —Br, and X³ is N. Inembodiments, X^(5.1) is —I, and X³ is N. In embodiments, X^(6.1) is —Cl,and X³ is N. In embodiments, X^(6.1) is —F, and X³ is N. In embodiments,X^(6.1) is —Br, and X³ is N. In embodiments, X^(6.1) is —I, and X³ is N.In embodiments, X^(7.1) is —Cl, and X³ is N. In embodiments, X^(7.1) is—F, and X³ is N. In embodiments, X^(7.1) is —Br, and X³ is N. Inembodiments, X^(7.1) is —I, and X³ is N. In embodiments, X^(8.1) is —Cl,and X³ is N. In embodiments, X^(8.1) is —F, and X³ is N. In embodiments,X^(8.1) is —Br, and X³ is N. In embodiments, X^(8.1) is —I, and X³ is N.In embodiments, X9.1 is —Cl, and X³ is N. In embodiments, X^(9.1) is —F,and X³ is N. In embodiments, X^(9.1) is —Br, and X³ is N. Inembodiments, X^(9.1) is —I, and X³ is N. In embodiments, X^(10.1) is—Cl, and X³ is N. In embodiments, X^(10.1) is —F, and X³ is N. Inembodiments, X^(10.1) is —Br, and X³ is N. In embodiments, X^(10.1) is—I, and X³ is N.

In embodiments, n1 is 0. In embodiments, n1 is 1. In embodiments, n1 is2. In embodiments, n1 is 3. In embodiments, n1 is 4. In embodiments, n2is 0. In embodiments, n2 is 1. In embodiments, n2 is 2. In embodiments,n2 is 3. In embodiments, n2 is 4. In embodiments, n3 is 0. Inembodiments, n3 is 1. In embodiments, n3 is 2. In embodiments, n3 is 3.In embodiments, n3 is 4. In embodiments, n3.2 is 0. In embodiments, n3.2is 1. In embodiments, n3.2 is 2. In embodiments, n3.2 is 3. Inembodiments, n3.2 is 4. In embodiments, n3.3 is 0. In embodiments, n3.3is 1. In embodiments, n3.3 is 2. In embodiments, n3.3 is 3. Inembodiments, n3.3 is 4. In embodiments, n4 is 0. In embodiments, n4is 1. In embodiments, n4 is 2. In embodiments, n4 is 3. In embodiments,n4 is 4. In embodiments, n5 is 0. In embodiments, n5 is 1. Inembodiments, n5 is 2. In embodiments, n5 is 3. In embodiments, n5 is 4.In embodiments, n6 is 0. In embodiments, n6 is 1. In embodiments, n6 is2. In embodiments, n6 is 3. In embodiments, n6 is 4. In embodiments, n7is 0. In embodiments, n7 is 1. In embodiments, n7 is 2. In embodiments,n7 is 3. In embodiments, n7 is 4. In embodiments, n8 is 0. Inembodiments, n8 is 1. In embodiments, n8 is 2. In embodiments, n8 is 3.In embodiments, n8 is 4. In embodiments, n8 is 0. In embodiments, n8is 1. In embodiments, n8 is 2. In embodiments, n8 is 3. In embodiments,n8 is 4. In embodiments, n9 is 0. In embodiments, n9 is 1. Inembodiments, n9 is 2. In embodiments, n9 is 3. In embodiments, n9 is 4.In embodiments, n10 is 0. In embodiments, n10 is 1. In embodiments, n10is 2. In embodiments, n10 is 3. In embodiments, n10 is 4.

In embodiments, m1 is 1. In embodiments, m1 is 2. In embodiments, v1is 1. In embodiments, v1 is 2. In embodiments, m2 is 1. In embodiments,m2 is 2. In embodiments, v2 is 1. In embodiments, v2 is 2. Inembodiments, m3 is 1. In embodiments, m3 is 2. In embodiments, v3 is 1.In embodiments, v3 is 2. In embodiments, m3.2 is 1. In embodiments, m3.2is 2. In embodiments, v3.2 is 1. In embodiments, v3.2 is 2. Inembodiments, m3.3 is 1. In embodiments, m3.3 is 2. In embodiments, v3.3is 1. In embodiments, v3.3 is 2. In embodiments, m4 is 1. Inembodiments, m4 is 2. In embodiments, v4 is 1. In embodiments, v4 is 2.In embodiments, m5 is 1. In embodiments, m5 is 2. In embodiments, v5is 1. In embodiments, v5 is 2. In embodiments, m6 is 1. In embodiments,m6 is 2. In embodiments, v6 is 1. In embodiments, v6 is 2. Inembodiments, m7 is 1. In embodiments, m7 is 2. In embodiments, v7 is 1.In embodiments, v7 is 2. In embodiments, m8 is 1. In embodiments, m8 is2. In embodiments, v8 is 1. In embodiments, v8 is 2. In embodiments, m9is 1. In embodiments, m9 is 2. In embodiments, v9 is 1. In embodiments,v9 is 2. In embodiments, m10 is 1. In embodiments, m10 is 2. Inembodiments, v10 is 1. In embodiments, v10 is 2.

In embodiments, z1 is 0. In embodiments, z1 is 1. In embodiments, z1 is2. In embodiments, z1 is 3. In embodiments, z1 is 4. In embodiments, z1is 5.

In embodiments, z2 is 0. In embodiments, z2 is 1. In embodiments, z2 is2. In embodiments, z2 is 3. In embodiments, z2 is 4. In embodiments, z2is 5.

In embodiments, z3 is 0. In embodiments, z3 is 1. In embodiments, z3 is2. In embodiments, z3 is 3. In embodiments, z3 is 4. In embodiments, z3is 5. In embodiments, z3 is 6. In embodiments, z3 is 7. In embodiments,z3 is 8. In embodiments, z3 is 9. In embodiments, z3 is 10. Inembodiments, z3 is 11.

In embodiments, z4 is 0. In embodiments, z4 is 1. In embodiments, z4 is2.

In embodiments, z1 is 2, z2 is 0, z4 is 1, and R⁷ is hydrogen,substituted or unsubstituted alkyl, phenyl, —F, —OH, —CH₂OH, —(CH₂)₂OH,—(CH₂)₃OH, —C(CH₃)₂OH, —CH₂SO₂NH₂, —(CH₂)₂SO₂NH₂, —CH₂C(O)NH₂,—(CH₂)₂C(O)NH₂, —(CH₂)₃C(O)NH₂, —CH₂NHSO₂CF₃, —(CH₂)₂NHSO₂CF₃,—(CH₂)₃NHSO₂CF 3,—CH₂NHSO₂CH3, —(CH₂)₂NHSO₂CH₃, —(CH₂)₃NHSO₂CH₃,—CH₂SO₂CH₃, —(CH₂)₂SO₂CH₃, —CH₂SO₂NH₂ or —(CH₂)₂SO₂NH₂.

In embodiments, R¹ and R² are independently hydrogen, substituted orunsubstituted alkyl or substituted or unsubstituted heteroalkyl. Inembodiments, R¹ and R² are independently hydrogen, R¹¹-substituted orunsubstituted alkyl or R¹¹-substituted or unsubstituted heteroalkyl. Inembodiments, R¹ and R² are hydrogen.

In embodiments, the compound has structural Formula (II):

or a pharmaceutically acceptable salt thereof, wherein R¹, R₂, R⁴, X²,X³, z4, and R⁷ as described herein, including embodiments. R^(3.2) andR^(3.3) may be are substituents encompassed by the definitions of R³. Inembodiments, R^(3.2) is hydrogen, halogen, —CX^(3.2) ₃, —CHX^(3.2) ₂,—CH₂X^(3.2), —CN, —N₃, SO_(n3.2)R^(3.2A), —SO_(v3.2)NR^(3.2B)R^(3.2C),—NHNR^(3.2B)R^(3.2C), —ONR^(3.2B)R^(3.2C), —NHC(O)NHNR^(3.2B)R^(3.2C),—NHC(O)NR^(3.2B)R3.2C, —N(O)_(m3.2), —NR^(3.2B)R^(3.2C), —C(O)R^(3.2)D,—C(O)OR^(3.2D), —C(O)NR^(3.2B)R^(3.2C), —OR^(3.2A),—NR^(3.2B)SO₂R^(3.2A), —NR^(3.2B)C(O)R^(3.2D), —NR^(3.2B)C(O)OR^(3.2D),—NR^(3.2B)OR^(3.2)D, —OCX^(3.2) ₃, —OCHX^(3.2) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R^(3.3) is hydrogen, halogen, —CX^(3.3) ₃,—CHX^(3.3) ₂, —CH₂X^(3.3), —CN, —N₃, —SO_(n3.3)R^(3.3A),—SO_(v3.3)NR^(3.3B)R^(3.3C), —NHNR^(3.3B)R^(3.3C), —ONR^(3.3B)R^(3.3C),—NHC(O)NHNR^(3.3B)R^(3.3C), —NHC(O)NR^(3.3B)R^(3.3C), —N(O)_(m3.3),—NR^(3.3B)R^(3.3C), —C(O)R^(3.3D), —C(O)OR^(3.3D),—C(O)NR^(3.3B)R^(3.3C), —OR^(3.3A), —NR^(3.3B)SO₂R^(3.3A),—NR^(3.3B)C(O)R^(3.3)_NR^(3. 3B)C(O)OR^(33D), —NR^(3.3B)OR^(3.3D),—OCX^(3.3) ₃, —OCHX^(3.3) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. Thesymbols n3.2, and n3.3 are independently an integer from 0 to 4. Thesymbols m3.2, m3.3, v3.2 and v3.3 are independently 1 or 2. Inembodiments, R⁴ is hydrogen, —CX^(4.1) ₃, —CN, —C(O)NR^(4B)R^(4C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

R^(3.2A), R^(3.2B), R^(3.2C), R^(3.2D), R^(3.3A), R^(3.3B), R^(3.3C) andR^(3.3D) are independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.R^(3.2B), R^(3.2C), R^(3.2B) and R^(3.2C) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; and X^(3.3) and X^(3.3) are independently —Cl, —Br, —I or—F.

In embodiments, the compound has structural Formula (IIa):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R⁴, X³,z4, L⁷, and R⁷ as described herein, including embodiments.

In embodiments, wherein the compound has structural Formula (IIb):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R⁴, X²,z4, L⁷, and R⁷ as described herein, including embodiments.

In embodiments, the compound has structural Formula (IIc):

or a pharmaceutically acceptable salt thereof wherein R¹, R², R⁴, z4,L⁷, and R⁷ as described herein, including embodiments. In embodiments,z4 is 1. In embodiments, R¹ and R² are independently hydrogen,substituted or unsubstituted alkyl or substituted or unsubstitutedheteroalkyl. In embodiments, R¹ is hydrogen. In embodiments, R² issubstituted or unsubstituted alkyl. In embodiments, R⁴ is hydrogen, —CN,—C(O)NH₂, —CX^(4.1) ₃ or substituted or unsubstituted alkyl. Inembodiments, R^(3.2) and R^(3.3) are independently halogen. Inembodiments, R^(3.2) and R^(3.3) are independently chlorine. Inembodiments, R⁷ is —OR^(7A), —C(O)R^(7D), —C(O)OR^(7D),—C(O)NR^(7B)R^(7C), SO_(n1)R^(7A), —SO_(v1)NR^(7B)R^(7C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl. In embodiments, L⁷ is a bond or substituted orunsubstituted alkylene. In embodiments, L⁷ is a bond. In embodiments, L⁷is a bond; and R⁷ is hydrogen, substituted or unsubstituted alkyl,phenyl, —(CH₂)₂OH, —CH₂C(CH₃)₂OH, —(CH₂)₃OH, —(CH₂)₂CH(CH₃)₂OH,—(CH₂)₂SO₂NH₂, —(CH₂)₃SO₂NH₂, —(CH₂)₂CONH₂, —(CH₂)₃CONH₂—(CH₂)₃CON(H)Me,—(CH₂)₃CON(Me)₂, —(CH₂)₂SO₂Me, —(CH₂)3SO₂Me, —CH₂CH(OH)Me, —CH₂CO₂H,—(CH₂)₂CO₂H, —CH(CH₃)CH₂CO₂H, —(CH₂)₃CO₂H, —(CH₂)2SO₂NHCH3,—(CH₂)₂SO₂N(CH₃)₂, —(CH₂)₂SO₂—(N- morpholinyl), —(CH₂)₂NHCOCH₃,—(CH₂)₃NHCOCH₃, —(CH₂)₂NHCOCH(CH₃)₂, —(CH₂)₂NHSO₂CH₃, —(CH₂)₂NHSO₂CF₃,—(CH₂)₂NHSO₂NHCH(CH₃)₂, —CH₂CH(CH₃)CH₂OH (R and S), —CH(CH₃)(CH₂)₂OH,—CH₂-(2-imidazoyl), —CH₂—(4-imidazoyl), —CH₂-(3-pyrazoyl),4-tetrahydropyranyl, 3-oxetanyl, —(CH₂)₂NHCO₂Me, —(CH₂)3NHCO₂Me.

In embodiments, the compound has structural Formula (IId):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R⁴, z4,L⁷, and R⁷ as described herein, including embodiments. In embodiments,z4 is 1. In embodiments, R¹ and R² are independently hydrogen,substituted or unsubstituted alkyl or substituted or unsubstitutedheteroalkyl. In embodiments, R¹ is hydrogen. In embodiments, R² issubstituted or unsubstituted alkyl. In embodiments, R⁴ is hydrogen, —CN,—C(O)NH₂, —CX^(4.1) ₃ or substituted or unsubstituted alkyl. Inembodiments, R⁴ is —CN, —C(O)NH₂, —CF₃ or —CH₃. In embodiments, R^(3.2)and R^(3.3) are independently halogen. In embodiments, R^(3.2) andR^(3.3) are independently chlorine. In embodiments, R⁷ is —OR^(7A),—C(O)R^(7D), —C(O)OR^(7D), —C(O)NR^(7B)R^(7C), —SO_(n1)R^(7A),—SO_(v1)NR^(7B)R^(7C), substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl. Inembodiments, L⁷ is a bond or substituted or unsubstituted alkylene. Inembodiments, L⁷ is a bond. In embodiments, L⁷ is a bond; and R⁷ ishydrogen, substituted or unsubstituted alkyl, phenyl, —(CH₂)₂OH,—CH₂C(CH₃)₂OH, —(CH₂)₃OH, —(CH₂)₂CH(CH₃)₂OH, —(CH₂)₂SO₂NH₂,—(CH₂)₃SO₂NH₂, —(CH₂)₂CONH₂, —(CH₂)₃CONH₂—(CH₂)₃CON(H)Me,—(CH₂)₃CON(Me)₂, —(CH₂)₂SO₂Me, —(CH₂)₃SO₂Me, —CH₂CH(OH)Me, —CH₂CO₂H,—(CH₂)₂CO₂H, —CH(CH₃)CH₂CO₂H, —(CH₂)₃CO₂H, —(CH₂)₂SO₂NHCH₃,—(CH₂)₂SO₂N(CH₃)2, —(CH₂)₂SO₂-(N-morpholinyl), —(CH₂)₂NHCOCH₃,—(CH₂)₃NHCOCH₃, —(CH₂)₂NHCOCH(CH₃)₂, —(CH₂)₂NHSO₂CH₃, —(CH₂)₂NHSO₂CF₃,—(CH₂)₂NHSO₂NHCH(CH₃)₂, —CH₂CH(CH₃)CH2OH (R and S), —CH(CH₃)(CH₂)₂OH,—CH₂-(2-imidazoyl), —CH₂-(4-imidazoyl), —CH₂-(3-pyrazoyl),4-tetrahydropyranyl, 3-oxetanyl, —(CH₂)₂NHCO₂Me, —(CH₂)₃NHCO₂Me.

In embodiments, the compound has structural Formula (III):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R⁴, R³,z1, X¹, X², X³, R⁵, z2, R⁶, z³, z4, L⁷, and R⁷ as described herein,including embodiments. In embodiments, R² is hydrogen. In embodiments,R¹ is hydrogen. In embodiments, R¹ is —CH₃.

In embodiments, the compound has structural Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R⁴,R^(3.2), R^(3.3), X², X³, z4, L⁷, and R⁷ as described herein, includingembodiments. In embodiments, R² is hydrogen. In embodiments, R¹ ishydrogen. In embodiments, R¹ is —CH₃.

In embodiments, the compound has structural Formula (V):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R₄,R^(3.2), R^(3.3), X², X³, z4, L⁷, and R⁷ as described herein, includingembodiments. In embodiments, R² is hydrogen. In embodiments, R¹ ishydrogen. In embodiments, R¹ is CH₃.

In embodiments, the compound has structural Formula (VI):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R⁴, X²,X³, L⁷, and R⁷ as described herein, including embodiments.

In embodiments, the compound has structural Formula (VII):

or a pharmaceutically acceptable salt thereof, wherein R⁴, R^(3.2),R^(3.3), X², X³, L⁷, and R⁷ as described herein, including embodiments.

In embodiments, the compound has the structure:

or a pharmaceutically acceptable salt thereof.

In embodiments, the compound has the structure:

or a pharmaceutically acceptable salt thereof.

In embodiments, the compound has the structure:

or a pharmaceutically acceptable salt thereof.

In embodiments, the compound has the structure:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound as described herein may include multipleinstances of a substituent (e.g., R³, R⁵, or R⁶ and/or other variables).In such embodiments, each variable may optional be different and beappropriately labeled to distinguish each group for greater clarity. Forexample, where each R³, R⁵, R⁶ is different, they may be referred to,for example, as R^(3.1), R^(3.2), R^(3.3) , R^(3.4), R^(3.5), R^(5.1),R^(5.2), R^(5.3), R^(5.4), or R^(6.1), R^(6.2), R^(6.3), R^(6.4),R^(6.5), R^(6.6), R^(6.7), R^(6.8), R^(6.9), or R^(6.10), respectively,wherein the definition of R³ is assumed by (independently assigned to)R^(3.1), R^(3.2), R^(3.3), R^(3.4), R^(3.5); R⁵ is assumed by(independently assigned to) R^(5.1), R^(5.2), R^(5.3), R^(5.4); or R⁶ isassumed by (independently, assigned to) R^(6.1), R^(6.2), R^(6.3),R^(6.4), R^(6.5), R^(6.6), R^(6.7), R^(6.8), R^(6.9), or R^(6.10). Thevariables used within a definition of R³, R⁵, or R⁶, and/or othervariables that appear at multiple instances and are different maysimilarly be appropriately labeled to distinguish each group for greaterclarity.

In embodiments, unless otherwise indicated, a compound described hereinis a racemic mixture of all stereoisomers. In embodiments, unlessotherwise indicated, a compound described herein is a racemic mixture ofall enantiomers. In embodiments, unless otherwise indicated, a compounddescribed herein is a racemic mixture of two opposite stereoisomers. Inembodiments, unless otherwise indicated, a compound described herein isa racemic mixture of two opposite enantiomers. In embodiments, unlessotherwise indicated, a compound described herein is a singlestereoisomer. In embodiments, unless otherwise indicated, a compounddescribed herein is a single enantiomer. In embodiments, the compound isa compound described herein (e.g., in an aspect, embodiment, example,figure, table, scheme, or claim).

III. Pharmaceutical Compositions

In an aspect is provided a pharmaceutical composition, including acompound as described herein, including embodiments, or the structuralFormula (I), (II), (IIa), (IIb), (IIc), (IId), (III), (IV), (V), (VI),or (VII), and a pharmaceutically acceptable excipient.

The compounds (e.g., CCR4 inhibitors) of the present invention may be inthe form of compositions suitable for administration to a subject. Ingeneral, such compositions are “pharmaceutical compositions” comprisinga compound (e.g., CCR4 inhibitor(s)) and one or more pharmaceuticallyacceptable or physiologically acceptable diluents, carriers orexcipients. In certain embodiments, the compound (e.g., CCR4 inhibitor)are present in a therapeutically acceptable amount. The pharmaceuticalcompositions may be used in the methods of the present invention; thus,for example, the pharmaceutical compositions can be administered ex vivoor in vivo to a subject in order to practice the therapeutic andprophylactic methods and uses described herein.

The pharmaceutical compositions of the present invention can beformulated to be compatible with the intended method or route ofadministration; exemplary routes of administration are set forth herein.

The pharmaceutical compositions containing the active ingredient (e.g.,an inhibitor of CCR4 function) may be in a form suitable for oral use,for example, as tablets, capsules, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsions, hard or softcapsules, or syrups, solutions, microbeads or elixirs. Pharmaceuticalcompositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions, and such compositions may contain one or more agents suchas, for example, sweetening agents, flavoring agents, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets, capsules and the like contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture thereof.These excipients may be, for example, diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc.

The tablets, capsules and the like suitable for oral administration maybe uncoated or coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction. For example, a time-delay material such as glyceryl monostearateor glyceryl distearate may be employed. They may also be coated bytechniques known in the art to form osmotic therapeutic tablets forcontrolled release. Additional agents include biodegradable orbiocompatible particles or a polymeric substance such as polyesters,polyamine acids, hydrogel, polyvinyl pyrrolidone, polyanhydrides,polyglycolic acid, ethylene-vinylacetate, methylcellulose,carboxymethylcellulose, protamine sulfate, or lactide/glycolidecopolymers, polylactide/glycolide copolymers, or ethylenevinylacetatecopolymers in order to control delivery of an administered composition.For example, the oral agent can be entrapped in microcapsules preparedby coacervation techniques or by interfacial polymerization, by the useof hydroxymethylcellulose or gelatin-microcapsules orpoly(methylmethacrolate) microcapsules, respectively, or in a colloiddrug delivery system. Colloidal dispersion systems include macromoleculecomplexes, nano-capsules, microspheres, microbeads, and lipid-basedsystems, including oil-in-water emulsions, micelles, mixed micelles, andliposomes. Methods for the preparation of the above-mentionedformulations will be apparent to those skilled in the art.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate, kaolin ormicrocrystalline cellulose, or as soft gelatin capsules wherein theactive ingredient is mixed with water or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture thereof. Such excipients can besuspending agents, for example sodium carboxymethylcellulose,methylcellulose, hydroxy-propylmethylcellulose, sodium alginate,polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents, for example a naturally-occurring phosphatide (e.g.,lecithin), or condensation products of an alkylene oxide with fattyacids (e.g., polyoxy-ethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols (e.g., forheptadecaethyleneoxycetanol), or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol (e.g.,polyoxyethylene sorbitol monooleate), or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides (e.g., polyethylene sorbitan monooleate). The aqueoussuspensions may also contain one or more preservatives.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents, such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, and optionally one or moresuspending agents and/or preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified herein.

The pharmaceutical compositions of the present invention may also be inthe form of oil-in-water emulsions. The oily phase may be a vegetableoil, for example olive oil or arachis oil, or a mineral oil, forexample, liquid paraffin, or mixtures of these. Suitable emulsifyingagents may be naturally occurring gums, for example, gum acacia or gumtragacanth; naturally occurring phosphatides, for example, soy bean,lecithin, and esters or partial esters derived from fatty acids; hexitolanhydrides, for example, sorbitan monooleate; and condensation productsof partial esters with ethylene oxide, for example, polyoxyethylenesorbitan monooleate.

The pharmaceutical compositions typically comprise a therapeuticallyeffective amount of a CCR4 inhibitor contemplated by the presentinvention and one or more pharmaceutically and physiologicallyacceptable formulation agents. Suitable pharmaceutically acceptable orphysiologically acceptable diluents, carriers or excipients include, butare not limited to, antioxidants (e.g., ascorbic acid and sodiumbisulfate), preservatives (e.g., benzyl alcohol, methyl parabens, ethylor n-propyl, p-hydroxybenzoate), emulsifying agents, suspending agents,dispersing agents, solvents, fillers, bulking agents, detergents,buffers, vehicles, diluents, and/or adjuvants. For example, a suitablevehicle may be physiological saline solution or citrate-buffered saline,possibly supplemented with other materials common in pharmaceuticalcompositions for parenteral administration. Neutral buffered saline orsaline mixed with serum albumin are further exemplary vehicles. Thoseskilled in the art will readily recognize a variety of buffers that canbe used in the pharmaceutical compositions and dosage forms contemplatedherein. Typical buffers include, but are not limited to,pharmaceutically acceptable weak acids, weak bases, or mixtures thereof.As an example, the buffer components can be water soluble materials suchas phosphoric acid, tartaric acids, lactic acid, succinic acid, citricacid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, andsalts thereof. Acceptable buffering agents include, for example, a Trisbuffer; N-(2-Hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) (HEPES);2-(N-Morpholino)ethanesulfonic acid (YMS);2-(N-Morpholino)ethanesulfonic acid sodium salt (YMS);3-(N-Morpholino)propanesulfonic acid (MOPS); andN-tris[Hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

After a pharmaceutical composition has been formulated, it may be storedin sterile vials as a solution, suspension, gel, emulsion, solid, ordehydrated or lyophilized powder. Such formulations may be stored eitherin a ready-to-use form, a lyophilized form requiring reconstitutionprior to use, a liquid form requiring dilution prior to use, or otheracceptable form. In some embodiments, the pharmaceutical composition isprovided in a single-use container (e.g., a single-use vial, ampule,syringe, or autoinjector (similar to, e.g., an EpiPen®)), whereas amulti-use container (e.g., a multi-use vial) is provided in otherembodiments.

Formulations can also include carriers to protect the compositionagainst rapid degradation or elimination from the body, such as acontrolled release formulation, including liposomes, hydrogels, prodrugsand microencapsulated delivery systems. For example, a time-delaymaterial such as glyceryl monostearate or glyceryl stearate alone, or incombination with a wax, may be employed. Any drug delivery apparatus maybe used to deliver a CCR4 inhibitor, including implants (e.g.,implantable pumps) and catheter systems, slow injection pumps anddevices, all of which are well known to the skilled artisan.

Depot injections, which are generally administered subcutaneously orintramuscularly, may also be utilized to release the compound (e.g.,CCR4 inhibitor) disclosed herein over a defined period of time. Depotinjections are usually either solid- or oil-based and generally compriseat least one of the formulation components set forth herein. One ofordinary skill in the art is familiar with possible formulations anduses of depot injections.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents mentioned herein. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example, as a solution in 1,3-butane diol. Acceptable diluents,solvents and dispersion media that may be employed include water,Ringer's solution, isotonic sodium chloride solution, Cremophor® EL(BASF, Parsippany, N.J.) or phosphate buffered saline (PBS), ethanol,polyol (e.g., glycerol, propylene glycol, and liquid polyethyleneglycol), and suitable mixtures thereof. In addition, sterile fixed oilsare conventionally employed as a solvent or suspending medium; for thispurpose, any bland fixed oil may be employed, including synthetic mono-or diglycerides. Moreover, fatty acids, such as oleic acid, find use inthe preparation of injectables. Prolonged absorption of particularinjectable formulations can be achieved by including an agent thatdelays absorption (e.g., aluminum monostearate or gelatin).

The present invention contemplates the administration of the compound(e.g., CCR4 inhibitor) in the form of suppositories for rectaladministration. The suppositories can be prepared by mixing the drugwith a suitable non-irritating excipient, which is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Such materials include, but arenot limited to, cocoa butter and polyethylene glycols.

The compound (e.g., CCR4 inhibitor) contemplated by the presentinvention may be in the form of any other suitable pharmaceuticalcomposition (e.g., sprays for nasal or inhalation use) currently knownor developed in the future.

IV. Methods of Use

In another aspect is provided a method of inhibiting C—C chemokinereceptor type 4

(CCR4), the method comprising contacting CCR4 with a compound asdescribed herein, including embodiments, or the structural Formula (I),(II), (IIa), (IIb), (IIc), (IId), (III), (IV), (V), (VI), or (VII) or apharmaceutically acceptable salt thereof.

In an aspect, is provided a method of treating or preventing a diseaseor disorder mediated by CCR4, comprising administering to a subject inneed thereof a therapeutically effective amount of a compound asdescribed herein, including embodiments, or the structural Formula (I),(II), (IIa), (IIb), (IIc), (IId, (III), (IV), (V), (VI), or (VII) or apharmaceutically acceptable salt thereof.

In embodiments, the method further includes administering atherapeutically effective amount of a compound as described herein,including embodiments, or the structural Formula (I), (II), (IIa),(IIb), (IIc), (IId), (III), (IV), (V), (VI), or (VII) or apharmaceutically acceptable salt thereof.

In embodiments, the method further includes administering atherapeutically effective amount of a compound as described herein,including embodiments, or the structural Formulae (I), (II), (IIa),(IIb), (IIc), (IId), (III), (IV), (V), (VI), or (VII) or apharmaceutically acceptable salt thereof.

In embodiments, the disease or disorder is an immune or inflammatorydisease or disorder. In embodiments, the methods of treating an immuneor inflammatory disease or disorder disclosed herein further includeco-administering an anti-inflammatory agent in combination with acompound of structural Formula (I), (II), (IIa), (IIb), (IIc), (IId),(III), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable saltthereof. In embodiments, the anti-inflammatory is thalidomide or aderivative thereof, a retinoid, dithranol or calcipotriol, anon-steroidal anti-inflammatory agent (NSAID), cyclo-oxygenaseinhibiting nitric oxide donors (CINODs), glucocorticosteroids,methotrexate, leflunomide, hydroxychloroquine, d-penicillamine,auranofin , analgesics; diacerein, hyaluronic acid derivatives ornutritional supplements.

In embodiments, the disease or disorder is a cardiovascular or metabolicdisease or disorder. In embodiments, the methods of treating acardiovascular or metabolic disease or disorder disclosed herein furtherinclude co-administering a cardiovascular agent or a metabolic disorderagent in combination with a compound of structural Formula (I), (II),(IIa), (IIb), (IIc), (IId), (III), (IV), (V), (VI), or (VII), or apharmaceutically acceptable salt thereof. In embodiments, thecardiovascular agent is a calcium channel blocker, a beta-adrenoceptorblocker, an angiotensin-converting enzyme (ACE) inhibitor, anangiotensin-2 receptor antagonist, a lipid lowering agent, a modulatorof blood cell morphology, a thrombolytic or an anticoagulant.

In embodiments, the disease or disorder is cancer. In embodiments, themethods of treating cancer disclosed herein further includeco-administering a chemotherapeutic agent or anticancer agent incombination with a compound of structural Formula (I), (II), (IIa),(IIb), (IIc), (IId), (III), (IV), (V), (VI), or (VII), or apharmaceutically acceptable salt thereof. In embodiments, thechemotherapeutic agent or anticancer agent is anantiproliferative/antineoplastic drug, an antimetabolite, an antitumourantibiotic, an antimitotic agent, a topoisomerase inhibitor, acytostatic agent, an oestrogen receptor down regulator, an antiandrogen,a LHRH antagonist or LHRH agonist, a progestogen, an aromataseinhibitor, an inhibitor of 5.alpha.-reductase, an agent which inhibitscancer cell invasion, an inhibitor of growth factor function, a farnesyltransferase inhibitor, a tyrosine kinase inhibitor, a serine/threoninekinase inhibitor, an inhibitor of the epidermal growth factor family, aninhibitor of the platelet-derived growth factor family, an inhibitor ofthe hepatocyte growth factor family; an antiangiogenic agent, a vasculardamaging agent, an agent used in antisense therapy, an anti-rasantisense, an agent used in a gene therapy, an immunotherapeutic agent,or an antibody. In embodiments, the methods of treating cancer disclosedherein further include co-administering a chemotherapeutic agent oranticancer agent in combination with a compound of structural Formula(I), (II), (IIa), (IIb), (IIc), (IId), (III), (IV), (V), (VI), or (VII),or a pharmaceutically acceptable salt thereof and a therapeuticallyeffective amount of at least two of: a CCR4 inhibitor, an inhibitor ofthe PD-L1/PD-1 pathway, an inhibitor of CTLA-4 or an agonistic antibodyof CD137 (4-1BB). In embodiments, the methods of treating cancerdisclosed herein further include co-administering a chemotherapeuticagent or anticancer agent in combination with a compound of structuralFormula (I), (II), (IIa), (IIb), (IIc), (IId, (III), (IV), (V), (VI), or(VII), or a pharmaceutically acceptable salt thereof and atherapeutically effective amount of at least two of: a CCR4 inhibitor,an immune modulator agent or an agent from Table 1, or any combinationthereof.

In embodiments, the disease or disorder is inflammatory bowel disease.In embodiments, the disease or disorder is rheumatoid arthritis. Inembodiments, the disease or disorder is psoriasis. In embodiments, thedisease or disorder includes allergy-related disorders (e.g.,hypersensitivity and anaphylactic responses); gastrointestinal disorders(e.g., Crohn's disease, ulcerative colitis, ileitis and enteritis);psoriasis and inflammatory dermatoses (e.g., dermatitis, eczema, atopicdermatitis, allergic contact dermatitis, dermatomyositis, urticaria andpruritus); vasculitis; scleroderma; asthma,

COPD, and respiratory allergic diseases (e.g., allergic rhinitis andhypersensitivity lung diseases); autoimmune diseases, includingarthritis (e.g., rheumatoid and psoriatic), multiple sclerosis, systemiclupus erythematosus, type I diabetes and glomerulonephritis; graftrejection (e.g., allograft rejection); transplant rejection (e.g., solidorgan); cancers, such as leukemias, lymphomas and metastatic cancers,particularly solid tumors (e.g., gastric cancers); and other diseases inwhich inhibition of undesired inflammatory and/or immune responses isdesired, such as atherosclerosis, neurodegenerative diseases (e.g.,Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis,sepsis, sarcoidosis, allergic conjunctivitis, otitis, and sinusitis. Inparticular embodiments, the CCR4-mediated disease, disorder or conditionis asthma, COPD, rhinitis, idiopathic pulmonary fibrosis, psoriasis andcontact dermatitis. In embodiments the disease or disorder is includingpulmonary fibrosis, hepatic inflammation, asthma, atopic dermatitis,cancer (e.g., thyroid carcinoma, cholangiocarcinoma, pancreaticadenocarcinoma, skin cutaneous melanoma, colon adenocarcinoma, rectumadenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head andneck squamous cell carcinoma, breast invasive carcinoma, lungadenocarcinoma, lung squamous cell carcinoma), or granuloma development.

In embodiments, the method further includes administering atherapeutically effective amount of a compound as described herein,including embodiments, or the structural Formula (I), (II), (IIa),(IIb), (IIc), (IId), (III), (IV), (V), (VI), or (VII) or apharmaceutically acceptable salt thereof.

In embodiments, the administration of the compounds disclosed herein forthe treatment or prevention of immune-, inflammatory-, or cancer-relateddiseases, disorders and conditions. Such diseases, disorders andconditions are described in detail elsewhere, as are other maladies thatmay be treated or prevented with compounds (e.g., CCR4 inhibitor)described herein.

It is frequently beneficial to improve one of more physical propertiesof the treatment modalities disclosed herein and/or the manner in whichthey are administered. Improvements of physical properties include, forexample, methods of increasing water solubility, bioavailability, serumhalf-life, and/or therapeutic half-life; and/or modulating biologicalactivity. Modifications known in the art include pegylation, Fc-fusionand albumin fusion. Although generally associated with large moleculeagents (e.g., polypeptides), such modifications have recently beenevaluated with particular small molecules. By way of example, Chiang, M.et al. (J. Am. Chem. Soc., 2014, 136(9):3370-73) describe a smallmolecule agonist of the adenosine 2a receptor conjugated to theimmunoglobulin Fc domain. The small molecule-Fc conjugate retainedpotent Fc receptor and adenosine 2a receptor interactions and showedsuperior properties compared to the unconjugated small molecule.Covalent attachment of PEG molecules to small molecule therapeutics hasalso been described (Li, W. et al., Progress in Polymer Science, 201338:421-44).

In embodiments, compounds of the present invention are effective in thetreatment and prevention of IBD (e.g., Crohn's disease and ulcerativecolitis, both of which are chronic idiopathic diseases that can affectany part of the gastrointestinal tract, and are associated with manyuntoward effects, and patients with prolonged ulcerative colitis are atan increased risk of developing colon cancer). Current IBD treatmentsare aimed at controlling inflammatory symptoms, and while certain agents(e.g., corticosteroids, aminosalicylates and standard immunosuppressiveagents (e.g., cyclosporine, azathioprine, and methotrexate)) have metwith limited success, long-term therapy may cause liver damage (e.g.,fibrosis or cirrhosis) and bone marrow suppression, and patients oftenbecome refractory to such treatments.

The compounds of the present invention can be used to increase orenhance an immune response; to improve immunization, includingincreasing vaccine efficacy; and to increase inflammation. Immunedeficiencies associated with immune deficiency diseases,immunosuppressive medical treatment, acute and/or chronic infection, andaging can be treated using the compounds disclosed herein. The compoundsdescribed herein can also be used to stimulate the immune system ofpatients suffering from iatrogenically-induced immune suppression,including those who have undergone bone marrow transplants,chemotherapy, or radiotherapy.

In accordance with the present invention, a compound or pharmaceuticalsalt thereof can be used to treat or prevent a proliferative conditionor disorder, including a cancer, for example, cancer of the uterus,cervix, breast, prostate, testes, gastrointestinal tract (e.g.,esophagus, oropharynx, stomach, small or large intestines, colon, orrectum), kidney, renal cell, bladder, bone, bone marrow, skin, head orneck, liver, gall bladder, heart, lung, pancreas, salivary gland,adrenal gland, thyroid, brain (e.g., gliomas), ganglia, central nervoussystem (CNS) and peripheral nervous system (PNS), and cancers of thehematopoietic system and the immune system (e.g., spleen or thymus). Thepresent invention also provides methods of treating or preventing othercancer-related diseases, disorders or conditions, including, forexample, immunogenic tumors, non-immunogenic tumors, dormant tumors,virus-induced cancers (e.g., epithelial cell cancers, endothelial cellcancers, squamous cell carcinomas and papillomavirus), adenocarcinomas,lymphomas, carcinomas, melanomas, leukemias, myelomas, sarcomas,teratocarcinomas, chemically-induced cancers, metastasis, andangiogenesis. The invention contemplates reducing tolerance to a tumorcell or cancer cell antigen, e.g., by modulating activity of aregulatory T-cell and/or a CD8+ T-cell (see, e.g., Ramirez-Montagut, etal. (2003) Oncogene 22:3180-87; and Sawaya, et al. (2003) New Engl. J.Med. 349:1501-09). In some embodiments, the tumor or cancer is coloncancer, ovarian cancer, breast cancer, melanoma, lung cancer,glioblastoma, or leukemia. In particular embodiments, the cancer isgastric cancer. The use of the term(s) cancer-related diseases,disorders and conditions is meant to refer broadly to conditions thatare associated, directly or indirectly, with cancer, and includes, e.g.,angiogenesis and precancerous conditions such as dysplasia. Inembodiments, the cancer is thyroid carcinoma, cholangiocarcinoma,pancreatic cancer, pancreatic adenocarcinoma, skin cutaneous melanoma,colon cancer, colon adenocarcinoma, rectum adenocarcinoma, stomachadenocarcinoma, esophageal carcinoma, head and neck squamous cellcarcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamouscell carcinoma.

In embodiments, a cancer be metastatic or at risk of becomingmetastatic, or may occur in a diffuse tissue, including cancers of theblood or bone marrow (e.g., leukemia). In some further embodiments, thecompounds of the invention can be used to overcome T-cell tolerance.

In some embodiments, the present invention provides methods for treatinga proliferative condition, cancer, tumor, or precancerous condition witha compound described herein and at least one additional therapeutic ordiagnostic agent, examples of which are set forth elsewhere herein.

The present invention provides methods for treating and/or preventing aproliferative condition, cancer, tumor, or precancerous disease,disorder or condition with a compound described herein.

In embodiments drawn to methods of treating cancer, the administrationof a therapeutically effective amount of a compound described hereinresults in a cancer survival rate greater than the cancer survival rateobserved by administering either agent alone. In further embodimentsdrawn to methods of treating cancer, the administration of atherapeutically effective amount of a compound described herein (e.g.,CCR4 inhibitor) results in a reduction of tumor size or a slowing oftumor growth greater than reduction of tumor size or tumor growthobserved following administration of either agent alone. In embodiments,the methods of treating cancer disclosed herein further includeadministering a chemotherapeutic agent or anticancer agent incombination with a compound of structural Formula (I), (II), (Ila),(IIb), (IIc), (IId), (III), (IV), (V), (VI), or (VII), or apharmaceutically acceptable salt thereof. In embodiments, thechemotherapeutic agent or anticancer agent is anantiproliferative/antineoplastic drug, an antimetabolite, an antitumourantibiotic, an antimitotic agent, a topoisomerase inhibitor, acytostatic agent, an oestrogen receptor down regulator, an antiandrogen,a LHRH antagonist or LHRH agonist, a progestogen, an aromataseinhibitor, an inhibitor of 5.alpha.-reductase, an agent which inhibitscancer cell invasion, an inhibitor of growth factor function, a farnesyltransferase inhibitor, a tyrosine kinase inhibitor, a serine/threoninekinase inhibitor, an inhibitor of the epidermal growth factor family, aninhibitor of the platelet-derived growth factor family, an inhibitor ofthe hepatocyte growth factor family; an antiangiogenic agent, a vasculardamaging agent, an agent used in antisense therapy, an anti-rasantisense, an agent used in a gene therapy, an immunotherapeutic agent,oran antibody. In embodiments, the methods of treating cancer disclosedherein further include co-administering a therapeutically effectiveamount of at least two of: a CCR4 inhibitor, an inhibitor of thePD-L1/PD-1 pathway, an inhibitor of CTLA-4 or an agonistic antibody ofCD137 (4-1BB). In embodiments, the methods of treating cancer disclosedherein further include co-administering a therapeutically effectiveamount of at least two of: a CCR4 inhibitor, an agent that may be animmune modulator or an agent from Table 1.

Inhibition of CCR4 activity may also represent an important strategy forthe treatment or prevention of neurological, neuropsychiatric,neurodegenerative or other diseases, disorders and conditions havingsome association with the central nervous system, including disordersassociated with impairment of cognitive function and/or motor function.Many of these diseases, disorders and conditions comprise an immuneand/or inflammatory component. In embodiments, the disease or disorderis Parkinson's disease, extra pyramidal syndrome (EPS), dystonia,akathisia, tardive dyskinesia, restless leg syndrome, epilepsy, periodiclimb movement in sleep, attention deficit disorders, depression,anxiety, dementia, Alzheimer's disease, Huntington's disease, multiplesclerosis, cerebral ischemia, hemorrhagic stroke, subarachnoidhemorrhage, or traumatic brain injury.

Embodiments of the present invention contemplate the administration ofthe compounds described herein to a subject for the treatment orprevention of any other disorder that may benefit from at least somelevel of CCR4 modulation. Such diseases, disorders and conditions mayinclude, for example, asthma, chronic obstructive pulmonary disease(COPD) including chronic bronchitis and emphysema, idiopathic pulmonaryfibrosis, atopic or contact dermatitis, urticaria, allergic rhinitis,nasal polyps, allergic conjunctivitis, thrombosis, reperfusion injury ofthe myocardium and brain, chronic glomerulonephritis, sepsis, adultrespiratory distress syndrome, and pain. Additional diseases, disordersand conditions include allergic bronchopulmonary aspergillosis, allergicfungal sinusitis, severe asthma with fungal sensitization and diseasesinvolving a pathogenic role for fungi including invasion or colonization(such as invasive aspergillosis, aspergilloma or candidiasis).

In embodiments, the disease or disorder includes cardiovascular (e.g.,cardiac ischemia), metabolic (e.g., development of insulititisdiabetes), hepatic (e.g., hepatic fibrosis, NASH, and NAFLD),ophthalmologic (e.g., diabetic retinopathy), and renal (e.g., renalfailure) disorders.

The present invention contemplates the administration of the compoundsdescribed herein, and compositions (e.g., pharmaceutical salts,pharmaceutical composition) thereof, in any appropriate manner. Suitableroutes of administration include oral, parenteral (e.g., intramuscular,intravenous, subcutaneous (e.g., injection or implant), intraperitoneal,intracisternal, intraarticular, intraperitoneal, intracerebral(intraparenchymal) and intracerebroventricular), nasal, vaginal,sublingual, intraocular, rectal, topical (e.g., transdermal), buccal andinhalation. Depot injections, which are generally administeredsubcutaneously or intramuscularly, may also be utilized to release thecompounds disclosed herein over a defined period of time. Inembodiments, the administration is oral administration.

The present invention provides methods for treating and/or preventingcertain cardiovascular-and/or metabolic-related diseases, disorders andconditions, as well as disorders associated therewith, with a compounddescribed herein.

The compounds of the present invention may be administered to a subjectin an amount that is dependent upon, for example, the goal ofadministration (e.g., the degree of resolution desired); the age,weight, sex, and health and physical condition of the subject to whichthe formulation is being administered; the route of administration; andthe nature of the disease, disorder, condition or symptom thereof. Thedosing regimen may also take into consideration the existence, nature,and extent of any adverse effects associated with the agent(s) beingadministered. Effective dosage amounts and dosage regimens can readilybe determined from, for example, safety and dose-escalation trials, invivo studies (e.g., animal models), and other methods known to theskilled artisan.

In general, dosing parameters dictate that the dosage amount be lessthan an amount that could be irreversibly toxic to the subject (themaximum tolerated dose (MTD)) and not less than an amount required toproduce a measurable effect on the subject. Such amounts are determinedby, for example, the pharmacokinetic and pharmacodynamic parametersassociated with ADME, taking into consideration the route ofadministration and other factors.

An effective dose (ED) is the dose or amount of an agent that produces atherapeutic response or desired effect in some fraction of the subjectstaking it. The “median effective dose” or ED50 of an agent is the doseor amount of an agent that produces a therapeutic response or desiredeffect in 50% of the population to which it is administered. Althoughthe ED50 is commonly used as a measure of reasonable expectance of anagent's effect, it is not necessarily the dose that a clinician mightdeem appropriate taking into consideration all relevant factors. Thus,in some situations the effective amount is more than the calculatedED50, in other situations the effective amount is less than thecalculated ED50, and in still other situations the effective amount isthe same as the calculated ED50.

In addition, an effective dose of the compounds of the present inventionmay be an amount that, when administered in one or more doses to asubject, produces a desired result relative to a healthy subject. Forexample, for a subject experiencing a particular disorder, an effectivedose may be one that improves a diagnostic parameter, measure, markerand the like of that disorder by at least about 5%, at least about 10%,at least about 20%, at least about 25%, at least about 30%, at leastabout 40%, at least about 50%, at least about 60%, at least about 70%,at least about 80%, at least about 90%, or more than 90%, where 100% isdefined as the diagnostic parameter, measure, marker and the likeexhibited by a normal subject.

In embodiments, the compounds contemplated by the present invention maybe administered (e.g., orally) at dosage levels of about 0.01 mg/kg toabout 50 mg/kg, or about 1 mg/kg to about 25 mg/kg, of subject bodyweight per day, one, two, three, four or more times a day, to obtain thedesired therapeutic effect. For administration of an oral agent, thecompositions can be provided in the form of tablets, capsules and thelike containing from 0.05 to 1000 milligrams of the active ingredient,particularly 0.05, 0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.5,5.0, 7.5, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 125.0, 150.0,175.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0,and 1000.0 milligrams of the active ingredient. A pharmaceuticallyacceptable carrier(s), diluent(s) and/or excipient(s) may be present inan amount of from about 0.1 g to about 2.0 g.

In embodiments, the dosage of the desired compound is contained in a“unit dosage form”. The phrase “unit dosage form” refers to physicallydiscrete units, each unit including a predetermined amount of thecompound (e.g., CCR4 inhibitor), sufficient to produce the desiredeffect. It will be appreciated that the parameters of a unit dosage formwill depend on the particular agent and the effect to be achieved.

V. Kits

In another aspect, provided herein is a kit including a compounddescribed herein (e.g., a CCR4 inhibitor) or pharmaceutical compositionsthereof. The kits are generally in the form of a physical structurehousing various components, as described below, and may be utilized, forexample, in practicing the methods described above.

A kit may include one or more of the compounds disclosed herein (e.g.,provided in a sterile container), which may be in the form of apharmaceutical composition suitable for administration to a subject. Thecompounds described herein (e.g., CCR4 inhibitors) can be provided in aform that is ready for use (e.g., a tablet or capsule) or in a formrequiring, for example, reconstitution or dilution (e.g., a powder)prior to administration. When the compound (e.g., CCR4 inhibitor) is ina form that needs to be reconstituted or diluted by a user, the kit mayalso include diluents (e.g., sterile water), buffers, pharmaceuticallyacceptable excipients, and the like, packaged with, or separately from,the compound. Each component of the kit may be enclosed within anindividual container, and all of the various containers may be within asingle package. A kit of the present invention may be designed forconditions necessary to properly maintain the components housed therein(e.g., refrigeration or freezing).

A kit may contain a label or packaging insert including identifyinginformation for the components therein and instructions for their use(e.g., dosing parameters, clinical pharmacology of the activeingredient(s), including mechanism of action, pharmacokinetics andpharmacodynamics, adverse effects, contraindications, etc.). Labels orinserts can include manufacturer information such as lot numbers andexpiration dates. The label or packaging insert may be, e.g., integratedinto the physical structure housing the components, contained separatelywithin the physical structure, or affixed to a component of the kit(e.g., an ampule, tube or vial).

Labels or inserts can additionally include, or be incorporated into, acomputer readable medium, such as a disk (e.g., hard disk, card, memorydisk), optical disk such as CD- or DVD-ROM/RAM, DVD, MP3, magnetic tape,or an electrical storage media such as RAM and ROM or hybrids of thesesuch as magnetic/optical storage media, FLASH media or memory-typecards. In some embodiments, the actual instructions are not present inthe kit, but means for obtaining the instructions from a remote source,e.g., via the internet, are provided.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

Additional Embodiments

Embodiments includes embodiment P1 to P41 following.

Embodiment P1. A compound having structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: X¹ is CR⁸ or N;X² is CR⁹ or N; X³ is CR¹⁰ or N; n1 and z3 are independently an integerfrom 0 to 4; m1 and v1 are independently 1 or 2; z1 is an integer from 0to 5; z2 is an integer from 0 to 2; z4 is an integer from 0 to 2; z⁷ isa bond, —O—, —S—, —NR^(7.2B)—, —C(O)—, —C(O)O—, —S(O) —, —S(O)₂—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, or substituted or unsubstituted heteroarylene; R¹ is hydrogen,halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1), —CN, —SO_(n1)R^(1A),—SO_(v1)NR_(1B)R^(1C), —NHNR^(1B)R^(1C), −ONR^(1B)R^(1C),—NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C), —N(O)_(m1),—NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A),—NR^(1B)SO₂R^(1A), —NR^(1B)C(O)_(R) ^(1D), —NR^(1B)C(O)OR^(1D),—NR^(1B)OR^(1D), OCX^(1.1) ₃, —OCHX^(1.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R² is hydrogen, halogen, —CX^(2.1) ₃,—CHX^(2.1) ₂, —CH₂X^(2.1), —CN, —SO_(n1)R^(2A), —SO_(v1)NR^(2B)R^(2C),—NHNR^(2B)R^(2C), —ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C),—NHC(O)NR²BR^(2C), —N(O)_(m1), —NR^(2B)R^(2C), —C(O)R^(2D),—C(O)OR^(2D), —C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A),—NR^(2B)C(O)R^(2D), —NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃,—OCHX^(2.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R³ ishydrogen, halogen, —CX^(3.1) ₃, —CHX^(3.1) ₂, —CH₂X^(3.1), —CN,—SO_(n1)R^(3A), —SO_(v1)NR^(3B)R^(3C), —NHNR^(3B)R^(3C),—ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C), —NHC(O)NR^(3B)R^(3C),—N(O)_(m1), —NR^(3B)R^(3C), —C(O)R^(3D), —C(O)OR^(3D),—C(O)NR^(3B)R^(3C), ——OR^(3A), —NR^(3B)SO₂R^(3A), —NR^(3B)C(O)R^(3D),—NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃, —OCHX^(3.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl; R⁴ is hydrogen, halogen,—CX^(4.1) ₃, —CHX4.1₂, —CH₂X^(4.1), —CN, —SO_(n1)R^(4A),—SO_(v1)NR^(4B)R^(4C), —NHNR^(4B)R^(4C), —ONR^(4B)R^(4C),—NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C), —N(O)_(m1),—NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D), —C(O)NR^(4B)R^(4C), —OR^(4A),—NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D), —NR^(4B)C(O)OR^(4D),—NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; R⁵ is hydrogen, halogen, oxo, —CX^(5.1) ₃,—CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —SO_(n1)R^(5A), —SO_(v1)NR^(5B)R^(5C),—NHNR^(5B)R^(5C), —ONR^(5B)R^(5C), —NHC(O)NHNR^(5B)R^(5C),—NHC(O)NR^(5B)R^(5C), N(O)_(m1), —NR^(5B)R^(5C), —C(O)R^(5D),—C(O)OR^(5D), —C(O)_(NR) ^(5B)R^(5C), —OR^(5A), —NR^(5B)SO₂R^(5A)_(, —)NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D), —NR^(5B)OR^(5D),—OCX^(5.1) ₃, OCHX^(5.1) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl or substituted or unsubstituted heteroaryl; R⁶ ishydrogen, halogen, oxo, —CX^(6.1) ₃, —CHX^(6.1) ₂, —CH₂X^(6.1), —CN,—SO_(n1)R^(6A), —SO_(v1)NR^(6B)R^(6C), —NHNR^(6B)R^(6C),—ONR^(6B)R^(6C), —NHC(O)NHNR^(6B)R^(6C), —NHC(O)NR^(6B)R^(6C),N(O)_(m1), —NR^(6B)R^(6C), —C(O)R^(6D), —C(O)OR^(6D),—C(O)NR^(6B)R^(6C)—OR^(6A), —NR^(6B)SO₂R^(6A), —NR^(6B)C(O)R^(6D),—NR^(6B)C(O)OR^(6D), —NR^(6B)OR^(6D), —OCX^(6.1) ₃, —OCHX^(6.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl; R⁷ is hydrogen, halogen,—CX^(7.1) ₃, —CHX^(7.1) ₂, —CH₂X^(7.1), —CN, —SO_(n1)R^(7A),—SO_(v1)NR^(7B)R^(7C), —NHNR^(7B)R^(7C), —ONR^(7B)R^(7C),—NHC(O)NHNR^(7B)R^(7C), —NHC(O)NR^(7B)R^(7C), —N(O)_(m1),—NR^(7B)R^(7C), —C(O)R^(7D), —C(O)OR^(7D), —C(O)NR^(7B)R^(7C), —OR^(7A),—NR^(7B)SO₂R^(7A), —NR^(7B)C(O)R^(7D), —NR^(7B)C(O)OR^(7D),—NR^(7B)OR^(7D), —OCX^(7.1) ₃, —OCHX^(7.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; R⁸ is hydrogen, halogen, —CX^(8.1) ₃,—CHX^(8.1) ₂, —CH₂X^(8.1), —CN, —SO_(n1)R^(8A), —SO_(v1)NR^(8B)R^(8C),—NHNR^(8B)R^(8C), —ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C),—NHC(O)NR^(8B)R^(8C), —N(O)_(m1), —NR^(8B)R^(8C), —C(O)R^(8D),—C(O)OR^(8D), —C(O)NR^(8B)R^(8C), —OR^(8A), —NR^(8B)SO₂R^(8A),—NR^(8B)C(O)R^(8D), —NR^(8B)C(O)OR^(8D), —NR^(8B)OR^(8D), —OCX^(8.1) ₃,—OCHX^(8.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁹ ishydrogen, halogen, —CX^(9.1) ₃, —CHX^(9.1) ₂, —CH₂X^(9.1), —CN,—SO_(n1)R^(9A), —SO_(v1)NR^(9B)R^(9C), —NHNR^(9B)R^(9C),—ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C), —NHC(O)NR^(9B)R^(9C),—N(O)_(m1), —NR^(9B)R^(9C), —C(O)R^(9D), —C(O)OR^(9D),—C(O)NR^(9B)R^(9C), —OR^(9A), —NR^(9B)SO₂R^(9A), —NR^(9B)C(O)R^(9D),—NR^(9B)C(O)OR^(9D), —NR^(9B)OR^(9D), —OCX^(9.1) ₃, —OCHX^(9.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R¹⁰ is hydrogen, halogen,—CX^(10.1) ₃, —CHX^(10.1) ₂, —CH₂X^(10.1), —CN, —SO_(n1)R^(10A),—SO_(v1)NR^(10B)R^(10C), —NHNR^(10B)R^(10C), —ONR^(10B)R^(10C),—NHC(O)NHNR^(10B)R^(10C), —NHC(O)NR^(10B)R^(10C), —N(O)_(m1),—NR^(10B)R^(10C), —C(O)R^(10D), —C(O)OR^(10D), —C(O)NR^(10B)R^(10C),—OR^(10A), —NR^(10B)SO₂R^(10A), —NR^(10B)C(O)R^(10D),—NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D), —OCX^(10.1) ₃, —OCHX^(10.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(1A), R^(1B), R^(1C), R^(1D),R^(2A), R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(3C), R^(3D), R^(4A),R^(4B), R^(4C), R^(4D), R^(5A), R^(5B), R^(5C), R^(5D), R^(6A), R^(6B),R^(6C), R^(6D), R^(7A), R^(7B), R^(7C), R^(7D), R^(7.2B), R^(8A),R^(8B), R^(8C), R^(8D), R^(9A), R^(9B), R^(9C), R^(9D), R^(10A),R^(10B), R^(10C), and R^(10D) are independently hydrogen, halogen, —CF₃,—CCl₃, —CBr₃, —CI₃, —COOH, —CONH₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(1B), R^(1C), R^(2B), R^(2C), R^(3B), R^(3C), R^(4B), R^(4C), R^(5B),R^(5C), R^(6B), R^(6C), R^(7B), R^(7C), R^(8B), R^(8C), R^(9B), R^(9C),R^(10B) and R^(10C) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; andX^(1.1), X^(2.1), X^(3.1), X^(4.1), X^(5.1), X^(6.1), X^(7.1), X^(8.1),X^(9.1) and X^(10.1) are independently —Cl, —Br, —I or —F, wherein atleast one of X¹, X² and X³ is N.

Embodiment P2. The compound of embodiment P1, wherein: z1 is 2; z2 is 0;z4 is 1; and R⁷ is hydrogen, substituted or unsubstituted alkyl, phenyl,—F, —OH, —CH₂OH, —(CH₂)₂OH, —(CH₂)₃OH, —C(CH₃)₂OH, —CH₂SO₂NH₂,—(CH₂)₂SO₂NH₂, —CH₂C(O)NH₂, —(CH₂)₂C(O)NH₂, —(CH₂)₃C(O)NH₂,—CH₂NHSO₂CF₃, —(CH₂)₂NHSO₂CF₃, —(CH₂)₃NHSO₂CF₃, —CH₂NHSO₂CH₃,—(CH₂)₂NHSO₂CH₃, —(CH₂)₃NHSO₂CH3,—CH₂SO₂CH3, —(CH₂)₂SO₂CH₃, —CH₂SO₂NH₂or —(CH₂)₂SO₂NH₂.

Embodiment P3. The compound of embodiment P2, wherein R¹ and R² areindependently hydrogen, substituted or unsubstituted alkyl orsubstituted or unsubstituted heteroalkyl.

Embodiment P4. The compound of embodiment P1, wherein the compound hasstructural Formula (II):

or a pharmaceutically acceptable salt thereof, wherein: R⁴ is hydrogen,—CX^(4.1) ₃, —CN, —C(O)NR^(4B)R^(4C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R^(3.2) is hydrogen, halogen, —CX^(3.2) ₃, —CHX^(3.2) ₂,—CH₂X^(3.2), —CN, —SO_(n1)R^(3.2A), —SO_(v1)NR^(3.2B)R^(3.2C),—NHNR^(3.2B)R^(3.2C), —ONR^(3.2B)R^(3.2C), —NHC(O)NHNR^(3.2B)R^(3.2C),—NHC(O)NR^(3.2B)R^(3.2C), —N(O)_(m1), NR^(3.2B)R^(3.2C), —C(O)R^(3.2D),C(O)OR^(3.2D), —C(O)NR^(3.2B)R^(3.2C), —OR^(3.2A),—NR^(3.2B)SO₂R^(3.2A), —NR^(3.2B)C(O)R^(3.2D), —NR^(3.2B)C(O)R^(3.2D),—NR^(3.2B)OR^(3.2D), —OCX^(3.2) ₃, —OCHX^(3.2) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(3.3) is hydrogen, halogen, —CX^(3.3) ₃,—CHX^(3.3) ₂, —CH₂X^(3.3), —CN, —SO_(n1)R^(3.3A),—SO_(v1)NR^(3.3B)R^(3.3C), —NHNR^(3.3B)R^(3.3C), —ONR^(3.3B)R^(3.3C),—NHC(O)NHNR^(3.3B)R^(3.3C), —NHC(O)NR^(3.3B)R^(3.3C), —N(O)_(m1),—NR^(3.3B)R^(3.3C), —C(O)R^(3.3D), —C(O)OR^(3.3D),—C(O)NR^(3.3B)R^(3.3C), —OR^(3.3A), —NR^(3.3B)SO₂R^(3.3A),—NR^(3.3B)C(O)R^(3.3D), —NR^(3.3B)C(O)OR^(3.3D), —NR^(3.3B)OR^(3.3D),—O—CX^(3.3) ₃, —OCHX^(3.3) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(3.2A), R^(3.2B), R^(3.2C), R^(3.2D), R^(3.3A), R^(3.3B), R^(3.3C) andR^(3.3D) are independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(3.2B), R^(3.2C), R^(3.2B) and R^(3.2C) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; and X^(3.2) and X^(3.3) are independently —Cl, —Br, —I or—F.

Embodiment P5. The compound of embodiment P4, wherein the compound hasstructural Formula (IIa):

or a pharmaceutically acceptable salt thereof.

Embodiment P6. The compound of embodiment P4, wherein the compound hasstructural Formula (IIb):

or a pharmaceutically acceptable salt thereof.

Embodiment P7. The compound of embodiment P5, wherein the compound hasstructural Formula (IIc):

or a pharmaceutically acceptable salt thereof.

Embodiment P8. The compound of embodiment P6, wherein the compound hasstructural Formula (IId):

or a pharmaceutically acceptable salt thereof.

Embodiment P9. The compound of embodiment P7 or P8, wherein z4 is 1.

Embodiment P10. The compound of embodiment P7 or P8, wherein R¹ and R²are independently hydrogen, substituted or unsubstituted alkyl orsubstituted or unsubstituted heteroalkyl.

Embodiment P11. The compound of embodiment P10, wherein R¹ is hydrogen.

Embodiment P12. The compound of embodiment P10, wherein R² issubstituted or unsubstituted alkyl.

Embodiment P13. The compound of embodiment P7 or P8, wherein R⁴ ishydrogen, —CN, —C(O)NH₂, —CX^(4.1) ₃ or substituted or unsubstitutedalkyl.

Embodiment P14. The compound of embodiment P13, wherein R⁴ is —CN,—C(O)NH₂, —CF₃ or CH₃.

Embodiment P15. The compound of embodiment P7 or P8, wherein R^(3.2) andR^(3.3) are independently halogen.

Embodiment P16. The compound of embodiment P15, wherein R^(3.2) andR^(3.3) are independently chlorine.

Embodiment P17. The compound of embodiment P7 or P8, wherein R⁷ is—OR^(7A), —C(O)R^(7D), —C(O)OR^(7D), —C(O)NR^(7B)R^(7C), —SO_(n1)R^(7A),—SO_(v1)NR^(7B)R^(7C), substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl.

Embodiment P18. The compound of embodiment P17, wherein L⁷ is a bond orsubstituted or unsubstituted alkylene.

Embodiment P19. The compound of embodiment P7 or P8, wherein: L⁷ is abond; and R⁷ is hydrogen, substituted or unsubstituted alkyl, phenyl,—(CH₂)₂OH, —CH₂C(CH₃)₂OH, —(CH₂)₃OH, —(CH₂)₂CH(CH₃)₂OH, (CH₂)₂SO₂NH₂,—(CH₂)₃SO₂NH₂, —(CH₂)₂CONH₂, —(CH₂)₃CONH₂ —(CH₂)₃CON(H)Me,—(CH₂)₃CON(Me)₂, —(CH₂)₂SO₂Me, —(CH₂)₃SO₂Me, —CH₂CH(OH)Me, —CH₂CO₂H,—(CH₂)₂CO₂H, —CH(CH₃)CH₂CO₂H, —(CH₂)₃CO₂H, —(CH₂)₂SO₂NHCH₃,—(CH₂)₂SO₂N(CH₃)₂, —(CH₂)₂SO₂—(N-morpholinyl), —(CH₂)₂NHCOCH₃,—(CH₂)3NHCOCH₃, —(CH₂)₂NHCOCH(CH₃)₂, —(CH₂)₂NHSO₂CH3, —(CH₂)₂NHSO₂CF ₃,—(CH₂)₂NHSO₂NHCH(CH₃)₂, —CH₂CH(CH₃)CH₂OH (R and S), —CH(CH₃)(CH₂)₂OH,—CH₂-(2-imidazoyl), —CH₂-(4-imidazoyl), —CH₂-(3-pyrazoyl),4-tetrahydropyranyl, 3-oxetanyl, —(CH₂)₂NHCO₂Me, —(CH₂)₃NHCO₂Me.

Embodiment P20. The compound of embodiment P1, wherein the compound hasstructural Formula (III):

or a pharmaceutically acceptable salt thereof.

Embodiment P21. The compound of embodiment P1, wherein the compound hasstructural Formula (IV):

or a pharmaceutically acceptable salt thereof.

Embodiment P22. The compound of embodiment P1, wherein the compound hasstructural Formula (V):

or a pharmaceutically acceptable salt thereof.

Embodiment P23. The compound of any one of embodiments P20 to P22,wherein R² is hydrogen.

Embodiment P24. The compound of any one of embodiments P20 to P22,wherein R¹ is hydrogen.

Embodiment P25. The compound of any one of embodiments P20 to P22,wherein R¹ is —CH₃.

Embodiment P26. The compound of embodiment P1, wherein the compound hasthe structure:

Embodiment P27. A pharmaceutical composition, comprising a compound ofstructural Formula (I) of embodiment P1 and a pharmaceuticallyacceptable excipient.

Embodiment P28. A method of inhibiting C—C chemokine receptor type 4(CCR4), the method comprising contacting CCR4 with a compound ofstructural Formula (I) of embodiment P1.

Embodiment P29. A method of treating or preventing a disease or disordermediated by CCR4, comprising administering to a subject in need thereofa therapeutically effective amount of a compound of structural Formula(I) of embodiment P1 or a pharmaceutically acceptable salt thereof.

Embodiment P30. The method of embodiment P29, wherein the disease ordisorder is an immune or inflammatory disease or disorder.

Embodiment P31. The method of embodiment P30, further comprisingco-administering an anti-inflammatory agent in combination with acompound of structural Formula (I).

Embodiment P32. The method of embodiment P31, wherein theanti-inflammatory is thalidomide or a derivative thereof, a retinoid,dithranol or calcipotriol, a non-steroidal anti-inflammatory agent(NSAID), cyclo-oxygenase inhibiting nitric oxide donors (CINODs),glucocorticosteroids, methotrexate, leflunomide, hydroxychloroquine,d-penicillamine, auranofin , analgesics; diacerein, hyaluronic acidderivatives or nutritional supplements.

Embodiment P33. The method of embodiment P29, wherein the disease ordisorder is a cardiovascular or metabolic disease or disorder.

Embodiment P34. The method of embodiment P33, further comprisingco-administering a cardiovascular agent or a metabolic disorder agent incombination with a compound of structural Formula (I).

Embodiment P35. The method of embodiment P31, wherein the cardiovascularagent is a calcium channel blocker, a beta-adrenoceptor blocker, anangiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptorantagonist, a lipid lowering agent, a modulator of blood cellmorphology, a thrombolytic or an anticoagulant.

Embodiment P36. The method of embodiment P29, wherein the disease ordisorder is cancer.

Embodiment P37. The method of embodiment P36, further comprisingco-administering a chemotherapeutic agent or anticancer agent incombination with a compound of structural Formula

(I).

Embodiment P38. The method of embodiment P37, wherein thechemotherapeutic agent or anticancer agent is anantiproliferative/antineoplastic drug, an antimetabolite, an antitumourantibiotic, an antimitotic agent, a topoisomerase inhibitor, acytostatic agent, an oestrogen receptor down regulator, an antiandrogen,a LHRH antagonist or LHRH agonist, a progestogen, an aromataseinhibitor, an inhibitor of 5.alpha.-reductase, an agent which inhibitscancer cell invasion, an inhibitor of growth factor function, a farnesyltransferase inhibitor, a tyrosine kinase inhibitor, a serine/threoninekinase inhibitor, an inhibitor of the epidermal growth factor family, aninhibitor of the platelet-derived growth factor family, an inhibitor ofthe hepatocyte growth factor family; an antiangiogenic agent, a vasculardamaging agent, an agent used in antisense therapy, an anti-rasantisense, an agent used in a gene therapy, an immunotherapeutic agent,or an antibody.

Embodiment P39. The method of embodiment P36, further comprisingco-administering a therapeutically effective amount of at least two of:a CCR4 inhibitor, an inhibitor of the PD-L1/PD-1 pathway, an inhibitorof CTLA-4 or an agonistic antibody of CD137 (4-1BB).

Embodiment P40. The method of embodiment P36, further comprisingco-administering a therapeutically effective amount of at least two of:a CCR4 inhibitor, an agent that may be an immune modulator or an agentfrom Table 1.

Embodiment P41. The method of any one of embodiments P37 to P40, whereinthe cancer is colon cancer or pancreatic cancer.

Further embodiments include embodiments 1 to 68 following.

Embodiment 1. A compound having structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: X¹ is CR⁸ or N;X² is CR⁹ or N; X³ is CR¹⁰ or N; n1, n2, n3, n4, n5, n6, n7, n8, n9, andn10 are independently an integer from 0 to 4; m1, m2, m3, m4, m5, m6,m7, m8, m9, m10, v1, v2, v3, v4, v5, v6, v7, v8, v9 and v10 areindependently 1 or 2; z1 is an integer from 0 to 5; z2 is an integerfrom 0 to 2; z3 is an integer from 0 to 11; z4 is an integer from 0 to2; L⁷ is a bond, —O—, —S—, —NR^(7.2B)—, —C(O)—, —C(O)O—, —S(O)—,—S(O)₂—, substituted or unsubstituted alkylene, substituted orunsubstituted heteroalkylene, substituted or unsubstitutedcycloalkylene, substituted or unsubstituted heterocycloalkylene,substituted or unsubstituted arylene, or substituted or unsubstitutedheteroarylene; R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂,—CH₂X^(1.1), —CN, —N₃, —SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C),—NHNR^(1B)R^(1C), —ONR^(1B) _(R) ^(1C), —NHC(O)NHNR^(1B)R^(1C),—NHC(O)NR^(1B)R^(1c), —N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D),—C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A),—NR^(1B)C(O)R^(1D), —NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃,—OCHX^(1.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R² ishydrogen, halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN, —N₃,—SO_(n2)R^(2A), —SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C),—ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C),—N(O)_(m2), —NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D),—C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D),—NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R³ is independently hydrogen,halogen, —CX^(3.1) ₃, —CHX^(3.1) ₂, —CH₂ ^(3.1), —CN, —N₃,—SO_(n1)R^(3A), —SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C),—ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C), —NHC(O)NR^(3B)R^(3C),—N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D), —C(O)OR^(3D), —C(O)_(NR)^(3B)R^(3V), OR^(3A), —NR^(3B)SO₂R^(3A), —NR^(3B)C(O)R^(3D),—NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃, —OCHX^(3.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl; R⁴ is hydrogen, halogen,—CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1), —CN, —N₃, —SO_(n4)R^(4A),—SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C), —ONR^(4B)R^(4C),—NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C), —N(O)_(m4),—NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D), —C(O)_(NR) ^(4B)R^(4C),—OR^(4A), —NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D), —NR^(4B)C(O)OR^(4D),—NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4,1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; R⁵ is independently hydrogen, halogen, oxo,—CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —N₃, —SO_(n5)R^(5A),—SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), —ONR^(5B)R^(5C),—NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C), —N(O)_(m5),—NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A),—NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D),—NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; R⁶ is independently hydrogen, halogen, oxo,—CX^(6.1) ₃, —CHX^(6.1) ₂, —CH₂X^(6.1), —CN, —N₃, —SO_(n6)R^(6A),—SO_(v6)NR^(6B)R^(6C), —NHNR^(6B)R^(6C), —ONR^(6B)R^(6C),—NHC(O)NHNR^(6B)R^(6C), —NHC(O)NR^(6B)R^(6C), —N(O)_(m6),—NR^(6B)R^(6C), —C(O)R^(6D), —C(O)OR^(6D), —C(O)NR^(6B)R^(6C), —OR^(6A),—NR^(6B)SO₂R^(6A), —NR^(6B)C(O)R^(6D), —NR^(6B)C(O)OR^(6D),—NR^(6B)OR^(6D), —OCX^(6.1) ₃, —OCHX^(6.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; R⁷ is hydrogen, halogen, —CX^(7.1) ₃,—CHX^(7.1) ₂, —CH₂X^(7.1), —CN, —N₃, —SO_(n7)R^(7A),—SO_(v7)NR^(7B)R^(7C), —NHNR^(7B)R^(7C), —ONR^(7B)R^(7C),—NHC(O)NHNR^(7B)R^(7C), —NHC(O)NR^(7B)R^(7C), —N(O)_(m7),—NR^(7B)R^(7C), —C(O)R^(7D), —C(O)OR^(7D), —C(O)NR^(7B)R^(7C), —OR^(7A),—NR^(7B)SO₂R^(7A), —NR^(7B)C(O)R^(7D), —NR^(7B)C(O)OR^(7D),—NR^(7B)OR^(7D), —OCX^(7.1) ₃, —OCHX^(7.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; R⁸ is hydrogen, halogen, —CX^(8.1) ₃,—CHX^(8.1) ₂, —CH₂X^(8.1), —CN, —N₃, —SO_(n8)R^(8A),—SO_(v8)NR^(8B)R^(8C), —NHNR^(8B)R^(8C), —ONR^(8B)R^(8C),—NHC(O)NHNR^(8B)R^(8C), —NHC(O)NR^(8B)R^(8C), —N(O)_(m8),—NR^(8B)R^(8C), —C(O)R^(8D), —C(O)OR^(8D), —C(O)NR^(8B)R^(8C), —OR^(8A),—NR^(8B)SO₂R^(8A), —NR^(8B)C(O)R^(8D), —NR^(8B)C(O)OR^(8D),—NR^(8B)OR^(8D), —OCX^(8.1) ₃, —OCHX^(8.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁹ is hydrogen, halogen, —CX^(9.1) ₃,—CHX^(9.1) ₂, —CH₂X^(9.1), —CN, —N₃, —SO_(n9)R^(9A),—SO_(v9)NR^(9B)R^(9V), —NHNR^(9B)R^(9C), —ONR^(9B)R^(9C),—NHC(O)NHNR^(9B)R^(9C), —NHC(O)NR^(9B)R^(9C), —N(O)_(m9),—NR^(9B)R^(9C), —C(O)R^(9D), —C(O)OR^(9D), —C(O)NR^(9B)R^(9C), —OR^(9A),—NR^(9B)SO₂R^(9A), —NR^(9B)C(O)R^(9D), —NR^(9B)C(O)OR^(9D),—NR^(9B)OR^(9D), —OCX^(9.1) ₃, —OCHX^(9.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R¹⁰ is hydrogen, halogen, —CX^(10.1) ₃,—CHX^(10.1) ₂, —CH₂X^(10.1), —CN, —N₃, —SO_(n10)R^(10A),—SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C), —ONR^(10B)R^(10C),—NHC(O)NHNR^(10B)R^(10C), —NHC(O)NR^(10B)R^(10C), —N(O)_(m10),—NR^(10B)R^(10C), —C(O)R^(10D), —C(O)OR^(10D), —C(O)NR^(10B)R^(10C),OR^(10A), —NR^(10B)SO₂R^(10A), —NR^(10B)C(O)R^(10D),—NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D), —OCX^(10.1) ₃, —OCHX^(10.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(1A), R^(1B), R^(1C), R^(1D),R^(2A), R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(3C), R^(3D), R^(4A),R^(4B), R^(4C), R^(4D), R^(5A), R^(5B), R^(5C), R^(5D), R^(6A), R^(6B),R^(6C), R^(6D), R^(7A), R^(7B), R^(7C), R^(7D), R^(7.2B), R^(8A),R^(8B), R^(8C), R^(8D), R^(9A), R^(9B), R^(9C), R^(9D), R^(10A),R^(10B), R^(10C) and R^(10D) are independently hydrogen, halogen, —CF₃,—CCl₃, —CBr₃, —CI₃, —COOH, —CONH₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(1B), R^(1C), R^(2B), R^(2C), R^(3B), R^(3C), R^(4A), R^(4C), R^(5B),R^(5C), R^(6B), R^(6C), R^(7B), R^(7C), R^(8B), R^(8C), R^(9B), R^(9C),R^(10B) and R^(10C) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; andX^(1.1), X^(2.1), X^(3.1), X^(4.1), X^(5.1), X^(6.1), X^(7.1), X^(8.1),X^(9.1) and X^(0.1) are independently —Cl, —Br, —I or —F, wherein atleast one of X¹, X² and X³ is N.

Embodiment 2. The compound of embodiment 1, or a pharmaceuticallyacceptable salt thereof, wherein: z1 is 2; z2 is 0; z4 is 1; and R⁷ ishydrogen, substituted or unsubstituted alkyl, phenyl, —F, —OH, CH₂OH,—(CH₂)₂OH, —(CH₂)₃OH, —C(CH₃)₂OH, —CH₂SO₂NH₂, —(CH₂)₂SO₂NH₂,—CH₂C(O)NH₂, —(CH₂)₂C(O)NH₂, —(CH₂)₃C(O)NH₂, —CH₂NHSO₂CF₃, —(CH₂)₂NHSO₂CF₃, —(CH₂)₃NHSO₂CF₃, —CH₂NHSO₂CH₃, —(CH₂)₂NHSO₂CH₃,—(CH₂)₃NHSO₂CH₃, —CH₂SO₂CH₃, —(CH₂)₂SO₂CH₃, —CH₂SO₂NH₂ or —(CH₂)₂SO₂NH₂.

Embodiment 3. The compound of embodiment 2, or a pharmaceuticallyacceptable salt thereof, wherein R¹ and R² are independently hydrogen,substituted or unsubstituted alkyl or substituted or unsubstitutedheteroalkyl.

Embodiment 4. The compound of embodiment 1, or a pharmaceuticallyacceptable salt thereof, wherein the compound has structural Formula(II):

wherein: n3.2, and n3.3 are independently an integer from 0 to 4; m3.2,m3.3, v3.2 and v3.3 are independently 1 or 2; R⁴ is hydrogen, —CX^(4.1)₃, —CN, —C(O)NR^(4B)R^(4C), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(3.2) is hydrogen, halogen, —CX^(3.2) ₃, —CHX^(3.2) ₂, —CH₂X^(3.2),—CN, —N₃, —SO_(n3.2)R^(3.2A), —SO_(v3.2)NR^(3.2B)R^(3.2C),—NHNR^(3.2B)R^(3.2C), —ONR^(3.2B)R^(3.2C), —NHC(O)NHNR^(3.2B)R^(3.2C),—NHC(O)NR^(3.2B)R^(3.2C), —N(O)_(m3.2), —NR^(3.2B)R^(3.2C),—C(O)R^(3.2D), —C(O)OR^(3.2D), —C(O)_(NR) ^(3.2B)R^(3.2C), —OR^(3.2A),—NR^(3.2B)SO₂R^(3.2A), —NR^(3.2B)C(O)R^(3.2D), —NR^(3.2B)C(O)OR^(3.2D),—NR^(3.2B)OR^(3.2D), 'OCX^(3.2) ₃, —OCHX^(3.2) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(3.3) is hydrogen, halogen, —CX^(3.3) ₃,—CHX^(3.3) ₂, —CH₂X^(3.3), —CN, —N₃, SO_(n3.3)R^(3.3A),—SO_(v3.3)NR^(3.3B)R^(3.3C), —NHNR^(3.3B)R^(3.3C), —ONR^(3.3B)R^(3.3C),—NHC(O)NHNR^(3.3B)R^(3.3C), —NHC(O)NR^(3.3B)R^(3.3C), —N(O)_(m3.3),—NR^(3.3B)R^(3.3C), —C(O)R^(3.3D), —C(O)OR^(3.3D),—C(O)NR^(3.3B)R^(3.3C), —OR^(3.3A), —NR^(3.3B)SO₂R^(3.3A),—NR^(3.3B)C(O)R^(3.3D), —NR^(3.3B)C(O)OR^(3.3D), —NR^(3.3B)OR^(3.3D),—OCX^(3.3) ₃, —OCHX^(3.3) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(3.2A), R^(3.2B), R^(3.2C), R^(3.2D), R^(3.3A), R^(3.3B), R^(3.3C) andR^(3.3D) are independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(3.2B), R^(3.2C), R^(3.2B) and R^(3.2C) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; and X^(3.2) and X^(3.3) are independently —Cl, —Br, —I or—F.

Embodiment 5. The compound of embodiment 4, or a pharmaceuticallyacceptable salt thereof, wherein the compound has structural Formula(IIa):

Embodiment 6. The compound of embodiment 4, or a pharmaceuticallyacceptable salt thereof, wherein the compound has structural Formula(IIb):

Embodiment 7. The compound of embodiment 5, or a pharmaceuticallyacceptable salt thereof, wherein the compound has structural Formula(IIc):

Embodiment 8. The compound of embodiment 6, or a pharmaceuticallyacceptable salt thereof, wherein the compound has structural Formula(IId):

Embodiment 9. The compound of embodiment 7 or 8, or a pharmaceuticallyacceptable salt thereof, wherein z4 is 1.

Embodiment 10. The compound of embodiment 7 or 8, or a pharmaceuticallyacceptable salt thereof, wherein R¹ and R² are independently hydrogen,substituted or unsubstituted alkyl or substituted or unsubstitutedheteroalkyl.

Embodiment 11. The compound of embodiment 10, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is hydrogen.

Embodiment 12. The compound of embodiment 10, or a pharmaceuticallyacceptable salt thereof, wherein R² is substituted or unsubstitutedalkyl.

Embodiment 13. The compound of embodiment 7 or 8, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is hydrogen, —CN, —C(O)NH₂,—CX^(4.1) ₃ or substituted or unsubstituted alkyl.

Embodiment 14. The compound of embodiment 13, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is CN, —C(O)NH2,—CF3 or CH₃.

Embodiment 15. The compound of embodiment 7 or 8, or a pharmaceuticallyacceptable salt thereof, wherein R^(3.2) and R^(3.3) are independentlyhalogen.

Embodiment 16. The compound of embodiment 15, or a pharmaceuticallyacceptable salt thereof, wherein R^(3.2) and R^(3.3) are independentlychlorine.

Embodiment 17. The compound of embodiment 7 or 8, or a pharmaceuticallyacceptable salt thereof, wherein R⁷ is —OR^(7A), —C(O)R^(7D),—C(O)OR^(7D), —C(O)NR^(7B)R^(7C), —SO_(n7)R^(7A), —SO_(v7)NR^(7B)R^(7C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl.

Embodiment 18. The compound of embodiment 17, or a pharmaceuticallyacceptable salt thereof, wherein L⁷ is a bond or substituted orunsubstituted alkylene.

Embodiment 19. The compound of embodiment 7 or 8, or a pharmaceuticallyacceptable salt thereof, wherein: L⁷ is a bond; and R⁷ is hydrogen,substituted or unsubstituted alkyl, phenyl, —(CH₂)₂OH, —CH₂C(CH₃)₂OH,—(CH₂)₃OH, —(CH₂)₂CH(CH₃)₂OH, —(CH₂)₂SO₂NH₂, —(CH₂)₃SO₂NH₂,——(CH₂)₂CONH₂, —(CH₂)₃CONH₂—(CH₂)₃CON(H)Me, —(CH₂)₃CON(Me)₂,—(CH₂)₂SO₂Me, —(CH₂)₃SO₂Me, —CH₂CH(OH)Me, —CH₂CO₂H, —(CH₂)₂CO₂H,—CH(CH₃)CH₂CO₂H, —(CH₂)₃CO₂H, —(CH₂)₂SO₂NHCH₃, —(CH₂)₂SO₂N(CH₃)₂,—(CH₂)₂SO₂-(N-morpholinyl), —(CH₂)₂NHCOCH₃, —(CH₂)₃NHCOCH₃,—(CH₂)₂NHCOCH(CH₃)₂, —(CH₂)₂NHSO₂CH₃, —(CH₂)₂NHSO₂CF₃,—(CH₂)₂NHSO₂NHCH(CH₃)₂, —CH₂CH(CH₃)CH₂OH (R and S), —CH(CH₃)(CH₂)₂OH,—CH₂-(2-imidazoyl), —CH₂-(4-imidazoyl), —CH₂-(3-pyrazoyl),4-tetrahydropyranyl, 3-oxetanyl, —(CH₂)₂NHCO₂Me, —(CH₂)₃NHCO₂Me.

Embodiment 20. The compound of embodiment 1, or a pharmaceuticallyacceptable salt thereof, wherein the compound has structural Formula(III):

Embodiment 21. The compound of embodiment 1, or a pharmaceuticallyacceptable salt thereof, wherein the compound has structural Formula(IV):

Embodiment 22. The compound of embodiment 1, or a pharmaceuticallyacceptable salt thereof, wherein the compound has structural Formula(V):

Embodiment 23. The compound of any one of embodiments 20 to 22, or apharmaceutically acceptable salt thereof, wherein R² is hydrogen.

Embodiment 24. The compound of any one of embodiments 20 to 22, or apharmaceutically acceptable salt thereof, wherein R¹ is hydrogen.

Embodiment 25. The compound of any one of embodiments 20 to 22, or apharmaceutically acceptable salt thereof, wherein R¹ is CH₃.

Embodiment 26. The compound of embodiment 1, or a pharmaceuticallyacceptable salt thereof, wherein the compound has the structure:

Embodiment 27. The compound of embodiment 1, or a pharmaceuticallyacceptable salt thereof, wherein the compound has the structure:

Embodiment 28. A pharmaceutical composition, comprising a compoundhaving structural Formula (I) and a pharmaceutically acceptableexcipient:

or a pharmaceutically acceptable salt thereof, wherein: X¹ is CR⁸ or N;X² is CR⁹ or N; X³ is CR¹⁰ or N; n1, n2, n3, n4, n5, n6, n7, n8, n9 andn10 are independently an integer from 0 to 4; m1, m2, m3, m4, m5, m6,m7, m8, m9, m10, v1, v2, v3, v4, v5, v6, v7, v8, v9 and v10 areindependently 1 or 2; z1 is an integer from 0 to 5; z2 is an integerfrom 0 to 2; z3 is an integer from 0 to 11; z4 is an integer from 0 to2; L⁷ is a bond, —O—, —S—, —NR^(7.2B)—, —C(O)—, —C(O)O—, —S(O)—,—S(O)₂—, substituted or unsubstituted alkylene, substituted orunsubstituted heteroalkylene, substituted or unsubstitutedcycloalkylene, substituted or unsubstituted heterocycloalkylene,substituted or unsubstituted arylene, or substituted or unsubstitutedheteroarylene; R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂,—CH₂X^(1.1), —CN, —N₃, —SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C),—NHNR^(1B)R^(1C), —ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C),—NHC(O)NR^(1B)R^(1C), —N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D),—C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A),—NR^(1B)C(O)R^(1D), —NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃,—OCHX^(1.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R² ishydrogen, halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN, —N₃,—SO_(n2)R^(2A), —SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C),—ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C),—N(O)_(m2), —NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D),—C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D),—NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R³ is independently hydrogen,halogen, —CX^(3.1) ₃, —CHX^(3.1) ₂, —CH₂X^(3.1), —CN, —N₃,—SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C),—ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C), —NHC(O)NR^(3B)R^(3C),—N(O)_(m3), —NR^(3B)R^(3C), -—

C(O)R^(3D), —C(O)OR^(3D), —C(O)NR^(3D), —C(O)OR^(3D),—C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A), —NR^(3B)C(O)R^(3D),—NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃, —OCHX³¹ ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl; R⁴ is hydrogen, halogen,—CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1), —CN, —N₃, —SO_(n4)R^(4A),—SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C), —ONR^(4B)R^(4C),—NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C), —N(O)_(m4),—NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D), —C(O)NR^(4B)R^(4C), —OR^(4A),—NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D), —NR^(4B)C(O)OR^(4D),—NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; R⁵ is independently hydrogen, halogen, oxo,—CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —N₃, —SO_(n5)R^(5A),—SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), —ONR^(5B)R^(5C),—NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C), —N(O)_(m5),—NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A),—NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D),—NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; R⁶ is independently hydrogen, halogen, oxo,—CX^(6.1) ₃, —CHX^(6.1) ₂, —CH₂X^(6.1), —CN, —N₃, —SO_(n6)R^(6A),—SO_(v6)NR^(6B)R^(6C), —NHNR^(6B)R^(6C), —ONR^(6B)R^(6C),—NHC(O)NHNR^(6B)R^(6C), —NHC(O)NR^(6B)R^(6C), —N(O)_(m6),—NR^(6B)R^(6C), —C(O)R^(6D), —C(O)OR^(6D), —CHX⁶¹ ₂, —CH₂X⁶¹, —C(O)_(NR)^(6B)R^(6C), —OR^(6A), —NR^(6B)SO₂R^(6A), —NR^(6B)C(O)R^(6D),—NR^(6B)C(O)OR^(6D), —NR^(6B)OR^(6D), —OCX^(6.1) ₃, —OCHX^(6.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl; R⁷ is hydrogen, halogen,—CX^(7.1) ₃, —CHX^(7.1) ₂, —CH₂X^(7.1), —CN, —N₃, —SO_(n7)R^(7A),—SO_(v7)NR^(7B)R^(7C), —NHNR^(7B)R^(7C), —ONR^(7B)R^(7C),—NHC(O)NHNR^(7B)R^(7C), —NHC(O)NR^(7B)R^(7C), —N(O)_(m7),—NR^(7B)R^(7C), —C(O)R^(7D), —C(O)OR^(7D), —C(O)NR^(7B)R^(7C), —OR^(7A),—NR^(7B)SO₂R^(7A), —NR^(7B)C(O)R^(7D), —NR^(7B)C(O)OR^(7D),—NR^(7B)OR^(7D), —OCX^(7.1) ₃, —OCHX^(7.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; R⁸ is hydrogen, halogen, —CX^(8.1) ₃,—CHX^(8.1) ₂, —CH₂X^(8.1), —CN, —N₃, —SO_(n8)R^(8A),—SO_(v8)NR^(8B)R^(8C), —NHNR^(8B)R^(8C), —ONR^(8B)R^(8C),—NHC(O)NHNR^(8B)R^(8C), —NHC(O)NR^(8B)R^(8C), —N(O)_(m8),—NR^(8B)R^(8C), —C(O)R^(8D), —C(O)OR^(8D), —C(O)NR^(8B)R^(8C), —OR^(8A),—NR^(8B)SO₂R^(8A), —NR^(8B)C(O)R^(8D), —NR^(8B)C(O)OR^(8D),—NR^(8B)OR^(8D), —OCX^(8.1) ₃, —OCHX^(8.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁹ is hydrogen, halogen, —CX^(9.1) ₃,—CHX^(9.1) ₂, —CH₂X^(9.1), —CN, —N₃, —SO_(n9)R^(9A),—SO_(v9)NR^(9B)R^(9C), —NHNR^(9B)R^(9C), —ONR^(9B)R^(9C),—NHC(O)NHNR^(9B)R^(9C), —NHC(O)NR^(9B)R^(9C), —N(O)_(m9),—NR^(9B)R^(9C), —C(O)R^(9D), —C(O)OR^(9D), —C(O)NR^(9B)R^(9C), —OR^(9A),—NR^(9B)SO₂R^(9A), —NR^(9B)C(O)R^(9D), —NR^(9B)C(O)OR^(9D),—NR^(9B)OR^(9D), —OCX^(9.1) ₃, —OCHX^(9.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R¹⁰ is hydrogen, halogen, —CX^(10.1) ₃,—CHX^(10.1) ₂, —CH₂X^(10.1), —CN, —N₃, —SO_(n10)R^(10A),—SO_(v10)NR^(10B)r^(10C), —NHNR^(10B)R^(10C), —ONR^(10B)R^(10C),—NHC(O)NHNR^(10B)R^(10C), —NHC(O)NR^(10B)R^(10C), —N(O)_(m10),—NR^(10B)R^(10C), —C(O)R^(10D), —C(O)OR^(10D), —C(O)NR^(10B)R^(10C),—OR^(10A), —NR^(10B)SO₂R^(10A), —NR^(10B)C(O)R^(10D),—NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D), —OCX^(10.1) ₃, —OCHX^(10.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(1A, R) ^(1B), R^(1C),R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(3C), R^(3D),R^(4A), R^(4B), R^(4C), R^(4D), R^(5A), R^(5B), R^(5C), R^(5D), R^(6A),R^(6B), R^(6C), R^(6D), R^(7A), R^(7B), R^(7C), R^(7D), R^(7.2B),R^(8A), R^(8B), R^(8C), R^(8D), R^(9A), R^(9B), R^(9C), R^(9D), R^(10A),R^(10B), R^(10C) and R^(10D) are independently hydrogen, halogen, —CF₃,—CCl₃, —CBr₃, —CI₃, —COOH, —CONH₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(1B), R_(1C), R^(2B), R^(2C), R^(3B), R^(3C), R^(4B), R^(4C), R^(5B),R^(5C), R^(6B), R^(6C), R^(7B), R^(7C), R^(8B), R^(8C), R^(9B), R^(9C),R^(10B) and R^(10C) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; andX^(1.1), X^(2.1), X^(3.1), X^(4.1), X^(5.1), X^(6.1), X^(7.1), X8.1,X^(9.1) and X^(10.1) are independently —Cl, —Br, —I or —F, wherein atleast one of X¹, X² and X³ is N.

Embodiment 29. A method of treating or preventing a disease or disordermediated by CCR4, comprising administering to a subject in need thereofa therapeutically effective amount of the pharmaceutical composition ofembodiment 28.

Embodiment 30. A method of inhibiting C—C chemokine receptor type 4(CCR4), comprising contacting CCR4 with a compound having structuralFormula (I):

or a pharmaceutically acceptable salt thereof, wherein: X¹ is CR⁸ or N;X² is CR⁹ or N; X³ is CR¹⁰ or N; n1, n2, n3, n4, n5, n6, n7, n8, n9 andn10 are independently an integer from 0 to 4; m1, m2, m3, m4, m5, m6,m7, m8, m9, m10, v1, v2, v3, v4, v5, v6, v7, v8, v9 and v10 areindependently 1 or 2; z1 is an integer from 0 to 5; z2 is an integerfrom 0 to 2; z3 is an integer from 0 to 11; z4 is an integer from 0 to2; L⁷ is a bond, —O—, —S—, —NR^(7.2B)—, —C(O)—, —C(O)O—, —S(O)—,—S(O)₂—, substituted or unsubstituted alkylene, substituted orunsubstituted heteroalkylene, substituted or unsubstitutedcycloalkylene, substituted or unsubstituted heterocycloalkylene,substituted or unsubstituted arylene, or substituted or unsubstitutedheteroarylene; R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂,—CH₂X^(1.1), —CN, —N₃, —SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C),—NHNR^(1B)R^(1C), —ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C),—NHC(O)NR^(1B)R^(1C), —N(O)_(m1), —NR^(1B)R^(1C), —C (O)OR^(1D),—C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A),—NR^(1B)C(O)R^(1D), —NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃,—OCHX^(1.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R² ishydrogen, halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN, —N₃,—SO_(n2)R^(2A), —SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C),—ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C),—N(O)_(m2), —NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D),—C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D),—NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R³ is independently hydrogen,halogen, —CX^(3.1) ₃, —CHX^(3.1) ₂, —CH₂X^(3.1), —CN, —N₃,—SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C),—ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C), —NHC(O)NR^(3B)R^(3C),—N(O)_(m3), —NR^(3B)R^(3C), C(O)R^(3D), —C(O)OR^(3D),—C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3b)SO₂R^(3A), —NR^(3B)C(O)R^(3D),—NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃, —OCHX^(3.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl; R⁴ is hydrogen, halogen,—CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1), —CN, —N₃, —SO_(n4)R^(4A),—SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C), —ONR^(4B)R^(4C),—NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C), —N(O)_(m4),—NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D), —C(O)NR^(4B)R^(4C), —OR^(4A),—NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D), —NR^(4B)C(O)OR^(4D),—NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; R⁵ is independently hydrogen, halogen, oxo,—CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —N₃, —SO_(n5)R^(5A),—SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), —ONR^(5B)R^(5C),—NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C), —N(O)_(m5),—NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A),—NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D),—NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; R⁶ is independently hydrogen, halogen, oxo,—CX^(6.1) ₃, —CHX^(6.1) ₂, —CH₂X^(6.1), —CN, —N₃, —SO_(n6)R^(6A),—SO_(v6)NR^(6B)R^(6C), —NHNR^(6B)R^(6C), —ONR^(6B)R^(6C),—NHC(O)NHNR^(6B)R^(6C), —NHC(O)NR^(6B)R^(6C), —N(O)_(m6),—NR^(6B)R^(6C), —C(O)R^(6D), —C(O)OR^(6D), —C(O)NR^(6B)R^(6C), OR^(6A),—NR^(6B)SO₂R^(6A), —NR^(6B)C(O)R^(6D), —NR^(6B)C(O)OR^(6D),—NR^(6B)OR^(6D), —OCX^(6.1) ₃, —OCHX^(6.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; R⁷ is hydrogen, halogen, —CX⁷¹ ₃, —CHX⁷¹ ₂,—CH₂X^(7.1), —CN, —N₃, —SO_(n7)R^(7A), —SO_(v7)NR^(7B)R^(7C),—NHNR^(7B)R^(7C), —ONR^(7B)R^(7C), —NHC(O)NHNR^(7B)R^(7X),—NHC(O)NR^(7B)R^(7C), —N(O)_(m7), —NR^(7B)R^(7C), —(O)R^(7D),—C(O)OR^(7D), —C(O)NR^(7B)R^(7C), —OR^(7A), —NR^(7B)SO₂R^(7A),—NR^(7B)C(O)R^(7D), —NR^(7B)C(O)OR^(7D), —NR^(7B)OR^(7D), —OCX^(7.1) ₃,—OCHX^(7.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl; R⁸ ishydrogen, halogen, —CX^(8.1) ₃, —CHX^(8.1) ₂, —CH₂X^(8.1), —CN, —N₃,—SO_(n8)R^(8A), —SO_(v8)NR^(8B)R^(8C), —NHNR^(8B)R^(8C),—ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C), —NHC(O)NR^(8B)R^(8C),—N(O)_(m8), —NR^(8B)R^(8C), —(O)R^(8D), —C(O)OR^(8D),—C(O)NR^(8B)R^(8C), —OR^(8A), —NR^(8B)SO₂R^(8A), —NR^(8B)C(O)R^(8D),—NR^(8B)C(O)OR^(8D), —NR^(8B)OR^(8D), —OCX^(8.1) ₃, —OCHX^(8.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁹ is hydrogen, halogen,—CX^(9.1) ₃, —CHX^(9.1) ₂, —CH₂X^(9.1), —CN, —N₃, —SO_(n9)R^(9A),—SO_(v9)NR^(9B)R^(9C), —NHNR^(9B)R^(9C), —ONR^(9B)R^(9C),—NHC(O)NHNR^(9B)R^(9C), —NHC(O)NR^(9B)R^(9C), —N(O)_(m9),—NR^(9B)R^(9C), —C(O)R^(9D), —C(O)OR^(9D), —C(O)NR^(9B)R^(9C), —OR^(9A),—NR^(9B)SO₂R^(9A), —NR^(9B)C(O)R^(9D), —NR^(9B)C(O)OR^(9D),—NR^(9B)OR^(9D), —OCX^(9.1) ₃, —OCHX^(9.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R¹⁰ is hydrogen, halogen, —CX^(10.1) ₃,—CHX^(10.1) ₂, —CH₂X^(10.1), —CN, —N₃, —SO_(n10)R^(10A),—SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C), —ONR^(10B)R^(10C),—NHC(O)NHNR^(10B)R^(10C), —NHC(O)NR^(10B)R^(10C), —N(O)_(m10),—NR^(10B)R^(10C), —C(O)R^(10D), —C(O)OR^(10D), —C(O)NR^(10B)R^(10C),—OR^(10A), —NR^(10B)SO₂R^(10A), —NR^(10B)C(O)R^(10D),—NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D), —OCX^(10.1) ₃, —OCHX^(10.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(1A), R^(1B), R^(1C), R^(1D),R^(2A), R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(3C), R^(3D), R^(4A),R^(4B), R^(4C), R^(4D), R^(5A), R^(5B), R^(5C), R^(5D), R^(6A), R^(6B),R^(6C), R^(6D), R^(7A), R^(7B), R^(7C), R^(7D), R^(7.2B), R^(8A),R^(8B), R^(8C), R^(8D), R^(9A), R^(9B), R^(9C), R^(9D), R^(10A),R^(10B), R^(10C) and R^(10C) are independently hydrogen, halogen, —CF₃,—CCl₃, —CBr₃, —CI₃, —COOH, —CONH₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(1B), R^(1C), R^(2B), R^(2C), R^(3B), R^(3C), R^(4A), R^(4C), R^(5B),R^(5C), R^(6B), R^(6C), R^(7B), R^(7C), R^(8B), R^(9B), R^(9C), R^(10B)and R^(10C) substituents bonded to the same nitrogen atom may optionallybe joined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; and X^(1.1), X^(2.1), X^(3.1),X^(4.1), X^(5.1), X^(6.1), X^(7.1), X^(8.1), X^(9.1) and X^(10.1) areindependently —Cl, —Br, —I or —F, wherein at least one of X¹, X² and X³is N.

Embodiment 31. A method of treating or preventing a disease or disordermediated by CCR4, comprising administering to a subject in need thereofa therapeutically effective amount of a compound having structuralFormula (I):

or a pharmaceutically acceptable salt thereof, wherein:X¹ is CR or N; X²is CR⁹ or N; X³ is CR¹⁰ or N; n1, n2, n3, n4, n5, n6, n7, n8, n9 and n10are independently an integer from 0 to 4; m1, m2, m3, m4, m5, m6, m7,m8, m9, m10, v1, v2, v3, v4, v5, v6, v7, v8, v9 and v10 areindependently 1 or 2; z1 is an integer from 0 to 5; z2 is an integerfrom 0 to 2; z3 is an integer from 0 to 11; z4 is an integer from 0 to2; L⁷ is a bond, —O—, —S—, —NR^(7.2B)—, —C(O)—, —C(O)O—, —S(O)—,—S(O)₂—, substituted or unsubstituted alkylene, substituted orunsubstituted heteroalkylene, substituted or unsubstitutedcycloalkylene, substituted or unsubstituted heterocycloalkylene,substituted or unsubstituted arylene, or substituted or unsubstitutedheteroarylene; R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂,—CH₂X^(1.1), —CN, —N₃, —SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C),—NHNR^(1B)R^(1C), —ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C),—NHC(O)NR^(1B)R^(1C), —N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D),—C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A),—NR^(1B)C(O)R^(1D), —NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃,—OCHX^(1.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R² ishydrogen, halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN, —N₃,—SO_(n2)R^(2A), —SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C),—ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C),—N(O)_(m2), —NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D),—C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D),—NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R³ is independently hydrogen,halogen, —CX^(3.1) ₃, —CHX^(3.1) ₂, —CH₂X^(3.1), —CN, —N₃,—SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C),—ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C), —NHC(O)NR^(3B)R^(3C),—N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D), —C(O)OR^(3D),—C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A), —NR^(3B)C(O)R^(3D),—NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃, —OCHX^(3.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl; R⁴ is hydrogen, halogen,—CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1), —CN, —N₃, —SO_(n4)R^(4A),—SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C), —ONR^(4B)R^(4C),—NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C), —N(O)_(m4),—NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D), —C(O)NR^(4B)R^(4C), —OR^(4A),—NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D), —NR^(4B)CO)OR^(4D),—NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; R⁵ is independently hydrogen, halogen, oxo,—CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —N₃, —SO_(n5)R^(5A),—SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), —ONR^(5B)R^(5C),—NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C), —N(O)_(m5),—NR^(5B)R^(5C), —(O)R^(5D), —C(O)OR^(5D), ——C(O)NR^(5B)R^(5C), —OR^(5A),—NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D),—NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; R⁶ is independently hydrogen, halogen, oxo,—CX^(6.1) ₃, —CHX^(6.1) ₂, —CH₂X^(6.1), —CN, —N₃, —SO_(n6)R^(6A),—SO_(v6)NR^(6B)R^(6C), —NHNR^(6B)R^(6C), —ONR^(6B)R^(6C),—NHC(O)NHNR^(6B)R^(6C), —NHC(O)NR^(6B)R^(6C), —N(O)_(m6),—NR^(6B)R^(6C), —C(O)R^(6D), —C(O)OR^(6D), ——C(O)NR^(6B)R^(6C),—OR^(6A), —NR^(6B)SO₂R^(6A), —NR^(6B)C(O)R^(6D), —NR^(6B)C(O)OR^(6D),—NR^(6B)OR^(6D), —OCX^(6.1) ₃, —OCHX^(6.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; R⁷ is hydrogen, halogen, —CX^(7.1) ₃,—CHX^(7.1) ₂, —CH₂X^(7.1), —CN, —N₃, —SO_(n7)R^(7A),—SO_(v7)NR^(7B)R^(7C) _(, NHNR) ^(7B) _(R) ^(7C), —ONR^(7B)R^(7C),—NHC(O)NHNR^(7B)R^(7C), —NHC(O)NR^(7B)R^(7C), —N(O)_(m7),—NR^(7B)R^(7C), —C(O)R^(7D), —C(O)OR^(7D), —C(O)NR^(7B)R^(7C), —OR^(7A),—NR^(7B)SO₂R^(7A), —NR^(7B)C(O)R^(7D), —NR^(7B)C(O)OR^(7D),—NR^(7B)OR^(7D), —OCX^(7.1) ₃, —OCHX^(7.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; R⁸ is hydrogen, halogen, —CX^(8.1) ₃,—CHX^(8.1) ₂, —CH₂X^(8.1), —CN, —N₃, —SO_(n8)R^(8A),—SO_(v8)NR^(8B)R^(8C), —NHNR^(8B)R^(8C), —ONR^(8B)R^(8C),—NHC(O)NHNR^(8B)R^(8C), —NHC(O)NR^(8B)R^(8C), —N(O)_(m8),—NR^(8B)R^(8C), —C(O)R^(8D), —C(O)OR^(8D), —C(O)NR^(8B)R^(8C), —OR^(8A),—NR^(8B)SO₂R^(8A), —NR^(8B)C(O)R^(8D), —NR^(8B)C(O)OR^(8D),—NR^(8B)OR^(8D), —OCX^(8.1) ₃, —OCHX^(8.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁹ is hydrogen, halogen, —CX^(9.1) ₃,—CHX^(9.1) ₂, —CH₂X^(9.1), —CN, —N₃, —SO_(n9)R^(9A),—SO_(v9)NR^(9B)R^(9C), —NHNR^(9B)R^(9C), —ONR^(9B)R^(9C),—NHC(O)NHNR^(9B)R^(9C), —NHC(O)NR^(9B)R^(9C), —N(O)_(m9),—NR^(9B)R^(9C), —C(O)R^(9D), —C(O)OR^(9D), —C(O)NR^(9B)R^(9C), —OR^(9A),—NR^(9B)SO₂R^(9A), 13 NR^(9B)C(O)R^(9D), —NR^(9B)C(O)R^(9D),—NR^(9B)OR^(9D), —OCX^(9.1) ₃, —OCHX^(9.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R¹⁰ is hydrogen, halogen, —CX^(10.1) ₃,—CHX^(10.1) ₂, —CH₂X^(10.1), —CN, —N₃, —SO_(n10)R^(10A),—SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C), —ONR^(10B)R^(10C),—NHC(O)NHNR^(10B)R^(10C), —NHC(O)NR^(10B)R^(10C), —N(O)_(m10),—NR^(10B)R^(10C), —C(O)R^(10D), —C(O)OR^(10D), —C(O)NR^(10B)R^(10C),—OR^(10A), —NR^(10B) _(SO) ₂R^(10A), —NR^(10B)C(O)R^(10D),—NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D), —OCX^(10.1) ₃, —OCHX^(10.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(1A), R^(1B), R^(1C), R^(1D),R^(2A), R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(3C), R^(3D), R^(4A),R^(4B), R^(4C), R^(4D), R^(5A), R^(5B), R^(5C), R^(5D), R^(6A), R^(6B),R^(6C), R^(6D), R^(7A), R^(7B)R^(7C), R^(7D), R^(7.2B), R^(8A), R^(8B),R^(8C), R^(8D), R^(9A), R^(9B), R^(9C), R^(9D), R^(10A), R^(10B),R^(10C) and R^(10D) are independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —COOH, —CONH₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(1B), R^(1C), R^(2B), R^(2C), R^(3B), R^(3C), R^(4B), R^(4C), R^(5B),R^(5C), R^(6B), R^(6C), R^(7B), R^(7C), R^(8B), R^(9B), R^(9C), R^(10B)and R^(10C) substituents bonded to the same nitrogen atom may optionallybe joined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; and X^(1.1), X^(2.1), X^(3.1),X^(4.1), X^(5.1), X^(6.1), X^(7.1), X^(8.1), X^(9.1) and X^(10.1) areindependently —Cl, —Br, —I or —F, wherein at least one of X¹, X² and X³is N.

Embodiment 32. The method of embodiment 31, wherein: z1 is 2; z4 is 1;and R⁷ is hydrogen, substituted or unsubstituted alkyl, phenyl, —F, —OH,CH₂OH, —(CH₂)₂OH, —(CH₂)₃OH, —C(CH₃)₂OH, —CH₂SO₂NH₂, —(CH₂)₂SO₂NH₂,—CH₂C(O)NH₂, —(CH₂)₂C(O)NH₂, —(CH₂)₃C(O)NH₂, —CH₂NHSO₂CF₃,—(CH₂)₂NHSO₂CF₃, —(CH₂)₃NHSO₂CF₃, —CH₂NHSO₂CH₃, —(CH₂)₂NHSO₂CH₃,—(CH₂)₃NHSO₂CH₃, —CH₂SO₂CH₃, —(CH₂)₂SO₂CH₃, —CH₂SO₂NH₂ or —(CH₂)₂SO₂NH₂.

Embodiment 33. The method of embodiment 32, wherein R¹ and R² areindependently hydrogen, substituted or unsubstituted alkyl orsubstituted or unsubstituted heteroalkyl.

Embodiment 34. The method of embodiment 31, wherein the compound hasstructural Formula (II):

or a pharmaceutically acceptable salt thereof, wherein: n3.2, and n3.3are independently an integer from 0 to 4; m3.2, m3.3, v3.2 and v3.3 areindependently 1 or 2; R⁴ is hydrogen, —CX^(4.1) ₃, —CN,—C(O)NR^(4B)R^(4C), substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R^(3.2)is hydrogen, halogen, —CX^(3.2) ₃, —CHX^(3.2) ₂, —CH₂X^(3.2), —CN, —N₃,—SO_(n3.2)R^(3.2A), —SO_(v3.2)NR^(3.2B)R^(3.2C), —NHNR^(3.2B)R^(3.2C),—ONR^(3.2B)R^(3.2C), —NHC(O)NHNR^(3.2B)R^(3.2C),—NHC(O)NR^(3.2B)R^(3.2C), —N(O)_(m3.2), —NR^(3.2B)R^(3.2C),—C(O)R^(3.2D), —C(O)OR^(3.2D), —C(O)NR^(3.2B)R^(3.2C), —OR^(3.2A),—NR^(3.2B)SO₂R^(3.2A), —NR^(3.2B)C(O)R^(3.2D), —NR^(3.2B)C(O)OR^(3.2D),—NR^(3.2B)OR^(3.2D), —OCX^(3.2) ₃, —OCHX^(3.2) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(3.3) is hydrogen, halogen, —CX^(3.3) ₃,—CHX^(3.3) ₂, —CH₂X^(3.3), —CN, —N₃, —SO_(n3.3)R_(3.3A),—SO_(v3.3)NR^(3.3B)R^(3.3C), —NHNR^(3.3B)R^(3.3C), —ONR^(3.3B)R^(3.3C),—NHC(O)NHNR^(3.3B)R^(3.3C), —NHC(O)NR^(3.3B)R^(3.3C), —N(O)_(m3.3),—NR^(3.3B)R^(3.3C), —C(O)R^(3.3D), —C(O)OR^(3.3D),—C(O)NR^(3.3B)R^(3.3C), —OR^(3.3A), —NR^(3.3B)SO₂R^(3.3A),—NR^(3.3B)C(O)R^(3.3D), —NR^(3.3B)C(O)OR^(3.3D), —NR^(3.3B)OR^(3.3D),—OCX^(3.3) ₃, —OCHX^(3.3) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(3.2A), R^(3.2B), R^(3.2C), R^(3.2D), R^(3.3A), R^(3.3B), R^(3.3C) andR^(3.3D) are independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—COOH, —CONH₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(3.2B), R^(3.2C), R^(3.2B) and R^(3.2C) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; and X^(3.2) and X^(3.3) are independently —Cl, —Br, —I or—F.

Embodiment 35. The method of embodiment 34, wherein the compound hasstructural Formula (IIa):

or a pharmaceutically acceptable salt thereof.

Embodiment 36. The method of embodiment 34, wherein the compound hasstructural Formula (IIb):

or a pharmaceutically acceptable salt thereof.

Embodiment 37. The method of embodiment 35, wherein the compound hasstructural Formula (IIc):

or a pharmaceutically acceptable salt thereof.

Embodiment 38. The method of embodiment 36, wherein the compound hasstructural Formula (IId):

or a pharmaceutically acceptable salt thereof.

Embodiment 39. The method of embodiment 37 or 38, wherein z4 is 1.

Embodiment 40. The method of embodiment 37 or 38, wherein R¹ and R² areindependently hydrogen, substituted or unsubstituted alkyl orsubstituted or unsubstituted heteroalkyl.

Embodiment 41. The method of embodiment 40, wherein R¹ is hydrogen.

Embodiment 42. The method of embodiment 40, wherein R² is substituted orunsubstituted alkyl.

Embodiment 43. The method of embodiment 37 or 38, wherein R⁴ ishydrogen, —CN, —C(O)NH₂, —CX^(4.1) ₃ or substituted or unsubstitutedalkyl.

Embodiment 44. The method of embodiment 43, wherein R⁴ is CN, —C(O)NH₂,—CF₃ or CH₃.

Embodiment 45. The method of embodiment 37 or 38, wherein R^(3.2) andR^(3.3) are independently halogen.

Embodiment 46. The method of embodiment 45, wherein R^(3.2) and R^(3.3)are independently chlorine.

Embodiment 47. The method of embodiment 37 or 38, wherein R⁷ is—OR^(7A), —C(O)R^(7D), —C(O)OR^(7D), —C(O)NR^(7B)R^(7C), —SO_(n7)R^(7A),—SO_(v7)NR^(7B)R^(7C), substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl.

Embodiment 48. The method of embodiment 47, wherein L⁷ is a bond orsubstituted or unsubstituted alkylene.

Embodiment 49. The method of embodiment 37 or 38, wherein: L⁷ is a bond;and R⁷ is hydrogen, substituted or unsubstituted alkyl, phenyl,—(CH₂)₂OH, —CH₂C(CH₃)₂OH, —(CH₂)₃OH, —(CH₂)₂CH(CH₃)₂OH, —(CH₂)₂SO₂NH₂,—(CH₂)₃SO₂NH₂, —(CH₂)₂CONH₂, —(CH₂)₃CONH₂, —(CH₂)₃CON(H)Me,—(CH₂)₃CON(Me)₂, —(CH₂)₂SO₂Me, —(CH₂)₃SO₂Me, —CH₂CH(OH)Me, —CH₂CO₂H,—(CH₂)₂CO₂H, —CH(CH₃)CH₂CO₂H, —(CH₂)₃CO₂H, —(CH₂)₂SO₂NHCH₃,—(CH₂)₂SO₂N(CH₃)₂, —(CH₂)₂SO₂—(N-morpholinyl), —(CH₂)₂NHCOCH₃,—(CH₂)₃NHCOCH₃, —(CH₂)₂NHCOCH(CH₃)₂, —(CH₂)₂NHSO₂CH₃, —(CH₂)₂NHSO₂CF ₃,—(CH₂)₂NHSO₂NHCH(CH₃)₂, —CH₂CH(CH₃)CH₂OH (R and S), —CH(CH₃)(CH₂)₂OH,—CH₂-(2-imidazoyl), —CH₂-(4-imidazoyl), —CH₂-(3-pyrazoyl),4-tetrahydropyranyl, 3-oxetanyl, —(CH₂)₂NHCO₂Me, —(CH₂)3NHCO₂Me.

Embodiment 50. The method of embodiment 31, wherein the compound hasstructural Formula (III):

or a pharmaceutically acceptable salt thereof.

Embodiment 51. The method of embodiment 31, wherein the compound hasstructural Formula (IV):

or a pharmaceutically acceptable salt thereof.

Embodiment 52. The method of embodiment 31, wherein the compound hasstructural Formula (V):

or a pharmaceutically acceptable salt thereof.

Embodiment 53. The method of any one of embodiments 50 to 52, wherein R²is hydrogen.

Embodiment 54. The method of any one of embodiments 50 to 52, wherein R¹is hydrogen.

Embodiment 55. The method of any one of embodiments 50 to 52, wherein R¹is —CH₃.

Embodiment 56. The method of embodiment 31, wherein the compound has thestructure:

or a pharmaceutically acceptable salt thereof.

Embodiment 57. The method of embodiment 31, wherein the disease ordisorder is an immune or inflammatory disease or disorder.

Embodiment 58. The method of embodiment 57, further comprisingco-administering an anti-inflammatory agent in combination with acompound of structural Formula (I) or a pharmaceutically acceptable saltthereof.

Embodiment 59. The method of embodiment 58, wherein theanti-inflammatory is thalidomide or a derivative thereof, a retinoid,dithranol, calcipotriol, a non-steroidal anti-inflammatory agent(NSAID), a cyclo-oxygenase inhibiting nitric oxide donor (CINOD), aglucocorticosteroid, methotrexate, leflunomide, hydroxychloroquine,d-penicillamine, auranofin, ananalgesic, a diacerein, hyaluronic acidderivative, or a nutritional supplement.

Embodiment 60. The method of embodiment 31, wherein the disease ordisorder is a cardiovascular or metabolic disease or disorder.

Embodiment 61. The method of embodiment 60, further comprisingco-administering a cardiovascular agent or a metabolic disorder agent incombination with a compound of structural Formula (I).

Embodiment 62. The method of embodiment 61, wherein the cardiovascularagent is a calcium channel blocker, a beta-adrenoceptor blocker, anangiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptorantagonist, a lipid lowering agent, a modulator of blood cellmorphology, a thrombolytic or an anticoagulant.

Embodiment 63. The method of embodiment 31, wherein the disease ordisorder is cancer.

Embodiment 64. The method of embodiment 63, further comprisingco-administering a chemotherapeutic agent or anticancer agent incombination with a compound of structural Formula (I).

Embodiment 65. The method of embodiment 64, wherein the chemotherapeuticagent or anticancer agent is an antiproliferative/antineoplastic drug,an antimetabolite, an antitumour antibiotic, an antimitotic agent, atopoisomerase inhibitor, a cytostatic agent, an oestrogen receptor downregulator, an antiandrogen, a LHRH antagonist or LHRH agonist, aprogestogen, an aromatase inhibitor, an inhibitor of 5.alpha.-reductase,an agent which inhibits cancer cell invasion, an inhibitor of growthfactor function, a farnesyl transferase inhibitor, a tyrosine kinaseinhibitor, a serine/threonine kinase inhibitor, an inhibitor of theepidermal growth factor family, an inhibitor of the platelet-derivedgrowth factor family, an inhibitor of the hepatocyte growth factorfamily; an antiangiogenic agent, a vascular damaging agent, an agentused in antisense therapy, an anti-ras antisense, an agent used in agene therapy, an immunotherapeutic agent, or an antibody.

Embodiment 66. The method of embodiment 65, further comprisingco-administering a therapeutically effective amount of at least two of:a CCR4 inhibitor, an inhibitor of the PD-L1/PD-1 pathway, an inhibitorof CTLA-4 or an agonistic antibody of CD137 (4-1BB).

Embodiment 67. The method of embodiment 65, further comprisingco-administering a therapeutically effective amount of at least two of:a CCR4 inhibitor, an immune modulator agent or an agent from Table 1, orany combination thereof.

Embodiment 68. The method of any one of embodiments 63 to 67, whereinthe cancer is colon cancer or pancreatic cancer.

EXAMPLES

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

The successful operation of the host defense system is the result ofseveral processes that work together to eliminate foreign pathogens.Coordinated innate and acquired immune responses are required, and manysecreted and cell-associated factors have been identified as importantmediators coordinating and regulating these two arms of host defense(see, e.g., Ness, T. et al. (2006) J Immunol 177:7531-39).

Chemokines are a family of cytokines that act as chemoattractants toguide leukocyte migration. They are secreted by a wide variety of cellsand can be functionally divided into two groups, hemostatic chemokinesand inflammatory chemokines. Hemostatic chemokines are constituentlyproduced in certain tissues and control cells of the immune systemduring processes of immune surveillance, such as directing lymphocytesto the lymph nodes to allow them to screen for invasion of pathogens.Inflammatory chemokines are released from cells in response to apathological event (e.g., pro-inflammatory stimuli such as IL-1 orviruses). They function primarily as chemoattractants as part of theinflammatory response and serve to guide cells of both the innate andadaptive immune systems to the site of inflammation. [See, e.g., Le, Y.et al. (2004) Cellular & Molec Immuno 1(2): 95-104 .]

Structurally, there are four subgroups of chemokines, classifiedaccording to the spacing of the first two cysteine residues: i) CCchemokines ((β-chemokines) have adjacent cysteines; ii) CXC chemokines(α-chemokines) having a single amino acid residue between the first twocysteines; iii) C chemokines (γ-chemokines) have only a singleN-terminal cysteine residue; and iv) CX₃C chemokines (δ-chemokines)having three amino acid residues between the first two cysteines. CCchemokines, examples of which include monocyte chemoattractant protein-1(MCP-1 or CCL2) and CCLS (RANTES), induce the migration of monocytes andother cell types; at least 27 members have been identified. CXCchemokines (some 17 in number) can be subdivided into two groups, bothof which have unique structural and functional features; the CXCchemokines bind to CXC chemokine receptors, of which 7 are known(designated CXCR1-7). Only two members of the C chemokine subgroup havebeen identified, XCL1 and XCL2 (lymphotactin-α and -β, respectively).Finally, the CX₃C chemokine subgroup has only one member, CX₃CL1, whichis both secreted and associated with the surface of the cells thatexpress it, resulting in both chemoattractant and adhesion properties.[See Sokol, C. and Luster, A. (2015) Cold Spring Harb Prospect Biol doi:10.1101/cshperspect.a016303.]

Chemokines bind to specific G protein-coupled receptors (“chemokinereceptors”), which are characterized by containing seven transmembranedomains, found on the surface of leukocytes (see Horuk (1994) TrendsPharm. Sci. 15:159-165). Approximately 20 human chemokine receptors havebeen identified, which are divided into four subgroups depending on thetype of chemokine they bind: CXCR bind CXC chemokines; CCR bind CCchemokines; CX3CR1 binds CX3CL1, the sole CXC3 chemokine; and XCR1 bindsXCL1 and XCL2, the two XC chemokines. Binding of a chemokine ligand toits cognate receptor triggers the receptor, resulting in dissociation ofan intracellular heterotrimeric G-protein complex into Gα and Gβγsubunits. These second messengers play an integral role in theactivation of several signaling cascades (e.g., the MAP kinase pathway),resulting in responses that include chemotaxis, inflammatory mediatorrelease, degranulation, and changes in cell shape. Chemokine receptorshave been implicated as being important mediators of inflammatory andimmunoregulatory disorders and diseases, including asthma and allergicdiseases, as well as autoimmune pathologies such as rheumatoid arthritisand atherosclerosis. [See, e.g., Comerford, I. and McColl, S. (2011)Immunol Cell Biol 89:183-84.]

The C—C chemokine receptor type 4 (CCR4), first identified by Power etal. (J. Biol. Chem. 270:19495-500 (1995)), plays a vital role in theprogression of a number of inflammation-related and other disorders(Gadhe, CG (February 2015) Mol Biosyst 11(2):618-34). CCR4 is a highaffinity receptor for the C—C-type chemokines CCL2 (MCP-1), CCL4(MIP-1), CCLS (RANTES), CCL17 (TARC), and CCL22 (MDC). Increasedexpression of CCR4 and its ligands is associated with the pathogenesisof a diverse array of diseases, including pulmonary fibrosis, hepaticinflammation, granuloma development, certain cancers and diabetes, eachof which is characterized by the infiltration of CCR4⁺ T cells intoaffected sites. The identification of compounds that modulate CCR4function provides an opportunity for the development of therapeuticagents for the treatment of a diverse array of diseases and disordersassociated with CCR4 activation.

The present invention relates to compounds that inhibit C—C chemokinereceptor type 4 (CCR4) activity, and compositions (e.g., pharmaceuticalcompositions) comprising the compounds. Such compounds, includingmethods of their synthesis, and compositions are described in detailherein. The present invention also relates to the use of such compoundsand compositions for the treatment and/or prevention of diseases,disorders and conditions mediated, in whole or in part, by CCR4.

Many subjects suffer from the debilitating effects of inflammatory-and/or immune-related disorders such as asthma and rheumatoid arthritis.Recently generated data support the role of inhibitors of CCR4 functionto modulate such inflammatory- and/or immune-related activity in atherapeutically beneficial manner. In addition, subjects diagnosed withcancer and the number of deaths attributable to cancer continue to rise,both in the US and abroad. Traditional treatment approaches comprisingchemotherapy and radiotherapy are generally difficult for the patient totolerate and become less effective as cancers (e.g., tumors) evolve tocircumvent such treatments.

Identification of CCR4 Inhibitors

In embodiments, compounds described herein possess at least one propertyor characteristic that is of therapeutic relevance. Candidate inhibitorsmay be identified by using, for example, an art-accepted assay or model.The Example section described assay(s) that were used to determine theCCR4 inhibitory activity of the compounds described herein, as well asassays that could be used to evaluate one or more characteristics of thecompounds; the skilled artisan is aware of other procedures, assayformats, and the like that can be employed to generate data andinformation useful to assess the CCR4 inhibitors described herein.

After identification, candidate inhibitors can be further evaluated byusing techniques that provide data regarding characteristics of theinhibitors (e.g., pharmacokinetic parameters). Comparisons of thecandidate inhibitors to a reference standard (which may the“best-of-class” of current inhibitors) are indicative of the potentialviability of such candidates. CCR4 inhibitors that can serve asreference or benchmark compounds include those shown to demonstratedesired activity and characteristics as described in, for example, USPatent Publn 2012/0015932 and PCT Publn 2013/082490. Other means ofanalyzing candidate inhibitors will be apparent to the skilled artisan.

Synthesis Details

The following general schemes represent synthetic methods that may beused in the preparation of the compounds of the present invention, aswell as common chemical intermediates generated in the preparationthereof. The skilled artisan will recognize that these schemes arerepresentative only, and that in many instances alternative syntheticmeans may be employed.

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the present invention, and are not intended to limit thescope of what the inventors regard as their invention, nor are theyintended to represent that the experiments below were performed or thatthey are all of the experiments that may be performed. It is to beunderstood that exemplary descriptions written in the present tense werenot necessarily performed, but rather that the descriptions can beperformed to generate data and the like of a nature described therein.Efforts have been made to ensure accuracy with respect to numbers used(e.g., amounts, temperature, etc.), but some experimental errors anddeviations should be accounted for.

Unless indicated otherwise, parts are parts by weight, molecular weightis weight average molecular weight, temperature is in degrees Celsius (°C.), and pressure is at or near atmospheric. Standard abbreviations areused, including the following: wt=wildtype; bp=base pair(s);kb=kilobase(s); nt=nucleotides(s); aa=amino acid(s); s or sec=second(s);min=minute(s); h or hr=hour(s); ng=nanogram; μg=microgram; mg=milligram;g=gram; kg=kilogram; dl or dL=deciliter; μl or μL=microliter; ml ormL=milliliter; 1 or L=liter; μM=micromolar; mM=millimolar; M=molar;kDa=kilodalton; i.m.=intramuscular(ly); i.p.=intraperitoneal(ly); SC orSQ=subcutaneous(ly); QD=daily; BID=twice daily; QW=weekly; QM=monthly;psi=pounds per square inch; HPLC=high performance liquid chromatography;BW=body weight; U=unit; ns=not statistically significant;HATU=(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate); TFA=trifluoroacetic acid; MBTE=methylt-butyl ether; DCM=dichloromethane; PBS=phosphate-buffered saline;IHC=immunohistochemistry; DMSO=dimethylsulfoxide; EtOAc=ethyl acetate;EtOH=ethanol; DMEM=Dulbeco's Modification of Eagle's Medium;EDTA=ethylenediaminetetraacetic acid; Me=methyl; Et=ethyl; S—singlet;D—doublet; dd—doublet of doublet; m—multiplet.

General preparation of the hydrazine starting material:

A substituted aminomethyl benzene of general structure 1 can be reactedwith an alkaline metal cyanate such as potassium cyanate in an acidifiedsolvent such as concentrated HCl. The resulting urea of generalstructure 2 can be isolated by standard methods such as filtration.After suitable purification, the urea of general structure 2 can bedissolved in a mixture of organic solvents such as toluene andtert-butanol and treated with t-butyl hypochlorite under a nitrogenatmosphere and the mixture is cooled to a temperature between −40 and 0°C. preferably around −20° C. The mixture is then warmed to 0° C. and theresulting solution is transferred to a flask containing a solution of analkoxide base such a potassium t-butoxide in a mixture of organicsolvents such as toluene and t-butanol which was being maintained attemperature between −40 and 0° C. preferably at −20° C. After theaddition the reaction is stirred for 15 min at a temperature of 0° C.and then poured onto ice water. The mixture is allowed to warm to roomtemperature over 20 min and is then extracted with an organic solventsuch as ethyl acetate. The organic extract is washed with water, anaqueous solution of sodium thiosulfate, and brine. The mixture is thenconcentrated to give the desired tert-butyl hydrazine carboxylateintermediate which can be immediate hydrolyzed in an acidic organicmixture such as HCl in dioxane for 8-24 h. Concentration of the solutionfollowed by trituration of the resulting residue with an organic solventsuch as ethyl acetate to give the desired hydrazine hydrochloride 3.

General synthesis of pyrazolopyrazine and pyridines:

A solution of hydrazine hydrochloride of general structure 3 in a proticorganic solvent such as ethanol is treated with the ketone of generalstructure 4. The mixture was stirred for 8 h at room temperature. Thereaction is concentrated under reduced pressure to give a residue. Theresidue was suspended in the mixture of organic solvents such as ethylacetate and hexanes and then filtered through a silica gel plug andeluted with a similar solvent mixture. The filtrate is concentrated togive the crude hydrazone of the general structure 5 as a mixture of Eand Z isomers. The mixture of E and Z hydrazine isomers of generalstructure 5 is dissolved in a polar aprotic solvent such asN-methyl-2-pyrrolidinone and treated with excess of a Lewis base, forexample 2,6-lutidine. The mixture is degassed with nitrogen and stirredunder a nitrogen atmosphere at an elevated temperature for example 100°C., for eight h. The reaction mixture is cooled to room temperature andthen poured into an acidic aqueous solution such as 1M HCl and theresulting mixture is extracted with an organic solvent such as ethylacetate. The layers were separated and the organic layer was washed withan acidic aqueous solution such as 1M HCl, dried over a drying agentsuch as magnesium sulfate, and concentrated under reduced pressure. Theresulting residue could be optionally be purified by recrystallizationor silica gel chromatography using a mixture of organic solvents forexample a mixture of MBTE and DCM to give compounds of the generalformula 6.

In certain instances, where ketone 4 is not commercially available, itcan be prepared in the following way:

A solution of halide of general structure 4a and a source of acetate inpolar aprotic solvent such as THF is treated with a strong alkalicomplex base such as LiTMP at low temperature −78° C. to afford 4 whichis used right away in the next step described in the previous procedureto afford compounds of the general formula 6.

A solution of halide of general structure 6 in an organic solvent suchas dioxane is treated with ammonia source such as ammonium hydroxide(29% in water). The mixture is stirred at room temperature for 3 d. Thereaction is diluted with a solvent such as ethyl acetate and washed witha weak aqueous base such as aqueous sodium carbonate. The organic layeris separated and dried over a drying agent such as magnesium sulfate.The organic layer is concentrated under reduced pressure to givecompounds of general formula 7. A solution of primary amide of generalstructure 7 in a polar aprotic organic solvent such as DCM at roomtemperature under innert atmosphere is added dehydration agent such asBurgess’ reagent. The mixture was stirred at room temperature for about2d. The resulting mixture can be purified by silica gel chromatographyusing a mixture of organic solvents for example a mixture of EtOAc andHexanes to give compounds of the general formula 8.

General synthesis of azetidine derivatives:

To a solution of the protected ketone of general structure 10 in anorganic solvent such as dichloroethane is added amine 9 and an iminereducing agent such as sodium triacetoxyborohydride and the mixture isstirred for between 4 and 18 h. The reaction is treated with a weakaqueous base such as aqueous sodium carbonate and the mixture isextracted with an organic solvent such as ethyl acetate. The organicsolvent is separated, treated with a drying agent such as sodium sulfateand the dried solution is evaporated to give amine of general structure11. The protective group on compound of general structure 11 can beexposed to an acidic organic solution, for example HCl in dioxane ortrifluoroacetic acid in DCM or can be removed using catalytic Pd. Themixture is stirred at room temperature for a time between one and 16 h.The reaction mixture can be concentrated or filtered through a celitepad and then concentrated under reduced pressure to give an amine saltof the general structure 12 that can be used in subsequent reactionswithout further purification.

Alternatively the piperidine 9 can be be reacted with an alkyl halideoptionally in the presence sodium iodide, in the presence of a base suchas sodium carbonate in a solvent such as DMF. After stirring between 4and 18 h, the reaction is diluted with water, and the mixture isextracted with an organic solvent such as ethyl acetate. The organicsolvent is separated, treated with a drying agent such as sodium sulfateand the dried solution is evaporated to give amine of general structure11. The protective group on compound of general structure 11 can beexposed to an acidic organic solution, for example HCl in dioxane ortrifluoroacetic acid in DCM or can be removed using catalytic Pd. Themixture is stirred at room temperature for a time between one and 16 h.The reaction mixture can be concentrated or filtered through a celitepad and then concentrated under reduced pressure to give an amine saltof the general structure 12 that can be used in subsequent reactionswithout further purification.

For instances where R⁸ contains electron withdrawing groups (EWG):

To a solution of amine of general structure 9 in dry organic solventsuch as DCM is added Michael acceptor 13. Reaction mixture was stirredeither at room temperature or at 50° C. until complete conversion whichcan be monitored using TLC or LCMS. Upon completion solvent is removed.The resulting residue can be purified by silica gel chromatography usinga mixture of organic solvents for example a mixture of MeOH and DCM togive compounds of the general formula 14. The protective group oncompound of general structure 14 can be exposed to an acidic organicsolution, for example HCl in dioxane or trifluoroacetic acid in DCM orcan be removed using catalytic Pd. The mixture is stirred at roomtemperature for a time between one and 16 h. The reaction mixture can beconcentrated or filtered through a celite pad and then concentratedunder reduced pressure to give an amine salt of the general structure 12that can be used in subsequent reactions without further purification.

Compounds of general formulas 12 and 6 in an organic solvent such as DMFare heated in the presence of a base such as di-isopropyl ethyl amine toa temperature ranging between 70 and ° C. for 1 hour. The reactionmixture can be partitioned between ethyl acetate and water containingTFA. The aqueous layer is evaporated and the resulting residue can bepurified by reversed phase preparative HPLC using a stationary phasesuch as C-18 and a solvent system such as varying amounts of water andacetonitrile containing 0.1% TFA. The resulting mixture of stereoisomerscould be converted to the free base by passing through amyberlyst resinand the basified amines purified using a chiral HPLC column such asChiracel OZ-H and the like using a mixture of organic solvents such asethanol and heptanes containing 0.1% diethyl amine as the solvent. Thepurified stereoisomers could be dissolved in ethanol and treated withHCl in ether and the solvents were removed under reduced pressure togive the desired compound 15 as HCl salt.

In certain instances where R⁸═—(CH₂),CO₂Et in compound 15 is dissolvedin an organic solvent such as MeOH and then treated with an alkali metalhydroxide such as LiOH and the resulting mixture is stirred for 3 h. Anaqueous acid such as 3M HCl is then added to the reaction. The mixtureis concentrated under reduced pressure and the resulting residue ispurified by reversed phase preparative HPLC using a stationary phasesuch as C-18 and a solvent system such as varying amounts of water andacetonitrile containing 0.1% TFA to give a compound of general structure16.

Precursor I. Preparation of(R)-6-chloro-1-(1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidineStep 1. Preparation of (R)-1-(2,4-dichlorophenyl)ethan-1-ol

To a solution of 2′,4′-dichloroacetophenone (10.9 g, 77.0 mmol) inanhydrous THF (80 mL) at −78° C. under nitrogen was slowly added asolution of (+)-B-chlorodiisopinocampheylborane ((+)-Ipc2BC1, 27.2, 85.0mmol) in THF (15 mL). After the addition is complete, the reactionmixture was slowly warmed to -25° C. and stirred at this temperature for2 h (monitored by TLC and LCMS). The reaction mixture was then quenchedwith diethanolamine (17.9 g, 170 mmol), and stirred for 10 min. Duringthis time, a solid formed and it was filtered off. The filtrate wasdried with Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified flash chromatography (SiO₂, 0-20% ethyl acetate in hexanes) togive (R)-1-(2,4-dichlorophenyl)ethanol. Yield 12.0 g, 63.3 mmol, 82%.Enantiomeric purity was determined on CHIRALPAK ID column, using 5%isopropanol in heptanes (98% ee, retention time 5.3 min). ¹H NMR (400MHz, CDCl₃) δ ppm 7.55 (d, J=8.4 Hz, 1H), 7.35 (t, J=2.2 Hz, 1H), 7.29(ddd, J=8.4, 2.1, 0.5 Hz, 1H), 5.26 (q, J=6.4 Hz, 1H), 1.47 (d, J=6.4Hz, 3H).

Step 2. Preparation of (S)-2,4-dichloro-1-(1-chloroethyl)benzene

To a stirred solution of N-chlorosuccinimide (11.0 g, 82.4 mmol) in THFat 0° C. (240 mL) was added triphenylphosphine (21.6 g, 82.4 mmol). Thereaction mixture was stirred at 0° C. for 10 min and then stirred atroom temperature for 30 min. The mixture was cooled to 0° C. and thenthe (R)-1-(2,4-dichlorophenyl)ethanol (12.0 g, 63.4 mmol) was added(dissolved in 25 mL of THF).

After the addition was completed, the mixture was allowed to warm up toroom temperature and stirred for an additional 3 h. The reaction mixturewas concentrated in vacuo and suspended in hexanes. The solid wasfiltered off and discarded. The filtrate was then concentrated in vacuoand the resulting residue was re-suspended in hexanes. The solid wasfiltered off and discarded. The filtrate was then concentrated in vacuoand the crude material was used without further purification. Yield 12.1g, 58 mmol, 91%. Enantiomeric purity was determined on CHIRALPAK IC-3column, using 100% heptanes (96% ee, retention time 4.5 min). ¹H NMR(400 MHz, CDCl₃) δ 7.59 (d, J=8.5 Hz, 1H), 7.39 (d, J=2.2 Hz, 1H), 7.30(dd, J=8.5, 2.2 Hz, 1H), 5.51 (q, J=6.8 Hz, 1H), 1.81 (d, J=6.8 Hz, 1H).

Step 3. Alkylation of 6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidinewith (S)-14-dichloro-1-(1-chloroethyl)benzene

6-Chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (500 mg, 2.97 mmol) wasdissolved in 10 mL of anhydrous DMF. Anhydrous Cs₂CO₃ (2.42 g, 7.43mmol) was added to the solution immediately followed by 1.74 g (8.91mmol) of (S)-2,4-dichloro-1-(1-chloroethyl)benzene (96% ee). Reactionmixture was allowed to stir at room temperature for 24 h and progresswas monitored by LCMS. Upon completion the reaction mixture was dilutedwith 20 mL of water and extracted 3 times with 20 mL of ethyl acetate.Combined organic fraction was dried with MgSO₄, filtered and purified bysilica gel chromatography using ethyl acetate and hexanes (0 to 100%gradient). Yield 500 mg, 49%. Enantiomeric purity determined by chiralHPLC using CHIRACEL OZ-H column 5% isopropanol in heptanes (retentiontime 6.9 min, 94% ee). ¹H NMR (400 MHz, DMSO-d6): δ ppm 9.27 (s, 1H),7.63-7.65 (m, 1H), 7.41-7.49 (m, 2H), 6.31 (q, J=7.0 Hz, 1H), 2.56 (s,3H), 1.83 (d, J=7.0 Hz, 3H). [M+H] 341.0.

Precursor II. Preparation of(R)-6-chloro-1-(1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazineStep 1. Preparation of (R)-1-(1-(2,4-dichlorophenyl)ethyl)urea

To a 6 L flask equipped with overhead stirrer was added(R)-1-(2,4-dichlorophenyl)ethan-1-amine (211 g, 1.11 mol)[reference WO2013082490], water (3.4 L) and concentrated HCl (92.5 mL, 1.11 mol). Themixture was a slurry. Then solid KOCN (90 g, 1.11 mol) was added in oneportion at rt. All solids went into solution and a white precipitatebegan to form after 1 h. The white precipitate was isolated byfiltration. The filtrate was allowed to stand at room temperature andmore precipitate formed. The precipitate was isolated by filtration.This was repeated several times until no more precipitate formed in thefiltrate upon standing at room temperature for 1 d. All the solids werecombined and dried under high vacuum.

Step 2. Preparation of (R)-(1-(2,4-dichlorophenyl)ethyl)hydrazinehydrochloride

(R)-1-(1-(2,4-dichlorophenyl)ethyl)urea (Example 5, Step 1, 50 g, 214.6mmol) was milled into a fine powder and placed into a 2 L flask. The 2 Lflask was purged with nitrogen gas and a degassed mixture of 1000 mL oftoluene and 375 mL of tBuOH added via cannula under nitrogen gas. KOtBu(240.3 g, 2146 mmol) was milled into fine powder and added to a separate5 L, 3 neck flask. The 5 L flask was purged with nitrogen, and adegassed mixture of 1000 mL of toluene and 650 mL of tBuOH was added viacannula under nitrogen gas. The 2 L and the 5 L mixtures were slurriesand were cooled to 20° C. The lights inside the hood were turned off.tBuOC1 (23.18 g, 24 mL, 214.6 mmol) was added to the 2 L flask at 20° C.Then the 20° C. bath was removed and the mixture was placed in a 0° C.bath. As soon as the slurry went all into solution, the mixture wastransferred to the 5 L flask via cannula under nitrogen at 20° C. Thelights in the hood were turned on. The 20° C. bath was removed, and themixture was placed into 0° C. bath. The mixture was stirred at 0° C. for10 min and then warmed to rt. The mixture was poured onto ice. Themixture was extracted with EtOAc (2×). The combined organic layers werewashed with 1 L water, 500 mL sat. sodium thiosulfate, and 1 L brine.The mixture was concentrated under reduced pressure to give tert-butyl(R)-2-(1-(2,4-dichlorophenyl)ethyl)hydrazine-1-carboxylate with 98.9%enantiomeric excess. Enantiomeric excess was determined by HPLC using aChiralpak® IF-3 column and eluting with 5% isopropanol in heptanes(retention time 5.3 min).

The residue was dissolved in 250 mL of 1.4-dioxane and HCl in1.4-dioxane (4 M, 161 mL, 643.8 mmol) was added at room temperature. Themixture was stirred at room temperature overnight and then concentratedunder reduced pressure. The residue was triturated from 25% EtOAc inhexanes (1 mL of solvent per 1 g of residue) to give(R)-(1-(2,4-dichlorophenyl)ethyl)hydrazine hydrochloride with 99.2%enantiomeric excess. Enantiomeric excess was determined by HPLC using aChiralpak® IF-3 column and eluting with 20% isopropanol in heptanes(retention time 4.7 min). ¹H NMR (400 MHz, CDCl₃, HCl salt) δ 7.75 (d,J=8.4 Hz, 1H), 7.43 (d, J=2.1 Hz, 1H), 7.35 (dd, J=8.4, 2.2 Hz, 1H),5.76 (b s, 4H), 4.91 (q, J=6.7 Hz, 1H), 1.64 (d, J=6.8 Hz, 3H). [M+H]205.2.

Step 3. Preparation of 3,5-dichloropyrazine-2-carboxamide

2,6-Dichloropyrazine (55 g, 0.37 mol) and formamide (300 mL) werecombined and heated to 90° C. Sodium persulfate (86.7 g, 0.36 mol) wasadded to the mixture at 90° C. in portions (˜1 g) 20-30 secondintervals. An exotherm was observed and the color of the mixture turnedfrom yellow to dark red/brown. The mixture was stirred at 90° C. for 2 hand then cooled to room temperature. The mixture was diluted with water(500 mL) and filtered. The filtrate layers were separated. The aqueouslayer was extracted with IPA/chloroform (1/3, 3×750 mL). The combinedorganic layers were dried over sodium sulfate and concentrated undervacuum to afford a viscous oil. The oil was purified by silica gelchromatography (0 to 100% EtOAc in hexanes) to provide the title productas a colorless solid (25 g, 36% yield). ¹H NMR (400 MHz, DMSO-d6): δ ppm8.87 (s, 1H), 8.18 (br. s., 1H), 8.01 (br. s., 1H).

Step 4. Preparation of 3,5-dichloropyrazine-2-carbonitrile

To a solution of 3,5-dichloropyrazine-2-carboxamide (Example 12, Step 2,52 g, 0.27 mol) in acetonitrile (1 L) was added POCl₃ (146 g, 89 mL,0.95 mol) at room temperature. The mixture was heated to 90-100° C. for4 h. The mixture was cooled to room tempetature and poured slowly into avigorously stirring solution of saturated aq. NaHCO₃. Evolution of gaswas observed. The mixture was extracted with EtOAc (3×). The combinedorganic layers were dried over sodium sulfate then concentrated underreduced pressure to give a residue. The residue was purified by silicagel chromatography (0-30% EtOAc in hexanes) to give the title compoundas a pale yellow solid. ¹H NMR (400 MHz, CDCl3): δ ppm 8.64 (s, 1H): ¹³CNMR (101 MHz, CDCl₃) δ ppm 150.8, 150.43, 143.24, 128.06, 113.06.

Step 5. Preparation of 1-(3,5-dichloropyrazin-2-yl)ethan-1-one

3,5-Dichloropyrazine-2-carbonitrile (Example 12, Step 2, 31.0 g, 178.18mmol) was dissolved in anhydrous diethyl ether (890 mL, 0.2 M) andcooled to −78° C. Then MeMgBr in diethyl ether (3.0 M, 65.3 mL, 190mmol) was added slowly to maintain low temperature. After the additionwas complete, the mixture was slowly warmed room temperature and stirredat room temperature for 1 h. The mixture was poured into a beakercontaining a mixture of HCl in water (1.0 M, 1 L) and ice (1 kg). Themixture was stirred vigorously for 10 min. The mixture was extractedwith diethyl ether (3×1 L). The combined organic layers were dried overNa₂SO₄ and concentrated under reduced pressure to afford the titlecompound as an orange oil (34 g, 99% yield). The mixture was used forthe next reaction without further purification. ¹H NMR (400 MHz, CDCl₃):δ ppm 8.56 (s, 1H), 2.71 (s, 3H).

Step 6. Preparation of(R,Z)-3,5-dichloro-2-(1-(2-(1-(2,4-dichlorophenyl)ethyl)hydrazono)ethyl)pyrazineand (R,E)-3,5-dichloro-2-(1-(2-(1-(2,4-dichlorophenyl)ethyl)hydrazono)ethyl)pyrazine

(R)-(1-(2,4-dichlorophenyl)ethyl)hydrazine hydrochloride (Example 5,Step 2, 47.3 g, 196 mmol) was dissolved in ethanol (356 mL, 0.5 M) atroom temperature, and then 1-(3,5-dichloropyrazin-2-yl)ethan-1-one (34.0g, 178 mmol) was added. The mixture was stirred at room temperature for8 h. The mixture was concentrated under reduced pressure to give aresidue. The residue was suspended in 20% EtOAc in hexanes (200 mL) andthen filtered through a silica gel plug and eluted using a 20% EtOAc inhexanes. The filtrate was concentrated under reduced pressure to givethe title products as a viscous orange oil.

Step 7. Cyclization of(R,Z)-3,5-dichlor-2-(1-(2-(1-(2,4-dichlorophenyl)ethyl)hydrazono)ethyl)pyrazineand(R,E)-3,5-dichloro-2-(1-(2-(1-(2,4-dichlorophenyl)ethyl)hydrazono)ethyl)pyrazine

A mixture of(R,Z)-3,5-dichloro-2-(1-(2-(1-(2,4-dichlorophenyl)ethyl)hydrazono)ethyl)pyrazineand (R,E)-3,5-dichloro-2-(1-(2-(1-(2,4-dichlorophenyl)ethyl)hydrazono)ethyl)pyrazine(9:1) (33 g, 87 mmol) was dissolved in N-methyl-2-pyrrolidone (218 mL)at room temperature. 2,6-Lutidine (30.3 mL, 262 mmol) was added. Themixture was degassed with nitrogen and then heated to 100° C. undernitrogen for 8 h. The reaction mixture was cooled to room temperatureand then poured into a separatory funnel containing 500 mL of HCl inwater (1 M) and 500 mL of ethyl acetate. The layers were separated andthe organic layer was washed with 500 mL of HCl in water (1 M), driedover MgSO₄, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (0 to 20% (1:1 MTBE:CH₂Cl₂) inhexanes) to provide the title compounds as off-white solid (67% yield).Enantiomeric purity was determined by HPLC using CHIRALPAK IA-3 andeluting with 5% isopropanol in heptanes. ¹H NMR (400 MHz, CDCl₃): δ ppm8.46 (s, 1H), 7.43 (d, J=8.5 Hz, 1H), 7.39 (d, J=2.2 Hz, 1H), 7.20 (dd,J=8.5, 2.2 Hz, 1H), 6.49 (q, J=7.1 Hz, 1H), 2.67 (s, 3H), 1.94 (d, J=7.1Hz, 3H); [M+H] 341.0.

Precursor III. Preparation of(R)-6-chloro-1-(1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carboxamide

Step 1. Preparation of Ethyl 2-(3,5-dichloropyrazin-2-yl)-2-oxoacetate

To a solution of 2,4,6-trimethylpyridine (67 mL, 0.40 moles) in THF (600mL) at −78° C. was added nBuLi (2.5 M in hexanes, 208 mL, 0.52 moles).The mixture was stirred at −78° C. for 20 min and then warmed to 0° C.In a separate flask, diethyloxalate (65 mL, 0.48 moles) and2,6-dichloropyrazine (60 g, 0.40 moles) were dissolved in THF (600 mL)and cooled to −78° C. The lithium 2,4,6-trimethylpyridine solution wasadded to the 2,6-dichloropyrazine solution via cannula over 1 h at −78°C. The mixture was stirred at −78° C. for 20 min and then the mixturewas poured into a mixture of sat. NH₄Cl (300 mL) and water (300 mL). Themixture was diluted with EtOAc (300 mL) and the layers were separated.The aqueous layer was extracted with EtOAc (300 mL) and the combinedorganic layers were dried over MgSO₄. The mixture was concentrated underreduced pressure. The residue was purified by silica gel chromatography(5 to 20% EtOAc in hexanes) to provide the title compound (32 g, 32%yield). ¹H NMR (400 MHz, DMSO-d6): δ ppm 8.87 (s, 1H), 8.18 (br. s.,1H), 8.01 (br. s., 1H).

Step 2. Preparation of Ethyl(R)-6-chloro-1-(1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carboxylate

To a solution of ethyl 2-(3,5-dichloropyrazin-2-yl)-2-oxoacetate (14.5g, 58.4 mmol) in THF (97 mL) was added(R)-(1-(2,4-dichlorophenyl)ethyl)hydrazine hydrochloride (Example 5,Step 2, 11.7 g, 48.7 mmol). The mixture was warmed to 80° C. for 2 h andthen cooled to room temperature. The mixture was allowed to stand atroom temperature under argon for 12 h. The mixture was diluted withbrine and the layers were separated. The aqueous layer was extractedwith EtOAc 2×. The combined organic layers were dried over MgSO₄ andconcentrated under reduced pressure to give a red oil.

The red oil was dissolved in THF (240 mL) and cooled to 0° C. Sodiumhydride (60% dispersion in mineral oil, 3.9 g, 97 mmol) was added andthe mixture was stirred at room temperature for 15 h. The mixture wasdiluted with sat. NH₄Cl (200 mL), water (200 mL), and EtOAc (200 mL).The layers were separated and the aqueous layer was extracted with EtOAc(100 mL). The combined organic layers were dried over MgSO₄ andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (10 to 20% EtOAc in hexanes) to provide the titlecompound (9.0 g, 46% yield) with >99% enantiomeric excess. Enantiomericexcess was determined by HPLC using a CHIRALPAK IF-3 column and elutingwith 5% isopropanol in heptanes (retention time 7.2 min).

Step 3. Reaction of ammonia with ethyl(R)-6-chloro-1-(1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carboxylate

To a solution of ethyl(R)-6-chloro-1-(1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carboxylate(4.0 g, 10 mmol) in dioxane (40 mL) at room temperature was addedammonium hydroxide (29% in water, 40 mL). The mixture was stirred in asealed tube at room temperature for 3 d. The mixture was diluted withsat. NaHCO₃. The mixture was extracted with EtOAc (2×). The combinedorganic layers were dried over MgSO₄ and concentrated under reducedpressure to give the title compound (3.4 g, 92% yield) as a light yellowsolid. ¹H NMR (400 MHz, DMSO-d6): δ ppm 8.87 (s, 1H), 7.93 (bs, 1H),7.84 (bs, 1H), 7.65-7.68 (m, 1H), 7.46-7.50 (m, 1H), 7.51-7.45 (m, 1H),6.49 (q, J=6.9 Hz, 1H), 1.91 (d, J=7.0 Hz, 3H); [M+H] 370.0.

Precursor IV.(R)-6-Chloro-1-(1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile

To a solution of(R)-6-chloro-1-(1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carboxamide(4.5 g, 12.2 mmol) in dichloromethane (30 mL) at room temperature underargon was added methyl N-(triethylammoniumsulfonyl)carbamate (Burgess'sreagent, 4.3 g, 18.1 mmol).

The mixture was stirred at room temperature for 2 d. The mixture waspreabsorbed onto silica gel and purified by chromatography (5% to 20%EtOAc in hexanes) to give the title compound (3.68 g, 88% yield) as asticky colorless solid. ¹H NMR (400 MHz, CDCl₃): δ ppm 8.69 (s, 1H),7.40-7.45 (m, 2H), 7.25-7.29 (m, 1H), 6.68 (q, J=7.0 Hz, 1H), 1.98 (d,J=7.1 Hz, 3H); [M+H] 351.9.

Precursor V.(R)-6-Chloro-1-(1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazineStep 1.(E)-3,5-Dichloro-2-(1-(2-(1-(2,4-dichlorophenyl)ethyphydrazono)-2,2,2-trifluoroethyl)pyrazineand (Z)-3,5-dichloro-2-(1-(2-(1-(2,4-dichlorophenyl)ethyl)hydrazono)-2,2,2-trifluoroethyl)pyrazine

To a solution of 2,2,6,6-tetramethylpiperidine (13.71 mL, 80.55 mmol) inTHF (200 mL) at −40° C. was added n-BuLi (2.5 M in hexanes, 34.91 mL,87.26 mmol). The mixture was stirred at −40° C. for 30 min. In aseparate flask, ethyl 2,2,2-trifluoroacetate (10.38 mL, 87.26 mmol) and2,6-dichloropyrazine (10.00 g, 67.13 mmol) were dissolved in THF (200mL) and cooled to −90° C. The lithium 2,2,6,6-tetramethylpiperidinesolution was added to the 2,6-dichloropyrazine solution via cannula over30 min at −90° C. The mixture was stirred at −90° C. for 30 min and(R)-(1-(2,4-dichlorophenyl)ethyl)hydrazine hydrochloride (Example 5,Step 2, 11.7g, 9.73 g, 40.28 mmol) was added, and then the mixture wasallowed to warm up to room temperature. The mixture was concentratedunder reduced pressure, then ethanol (200 mL) was added and the mixturewas stirred at room temperature for 24 h. The mixture was concentratedunder reduced pressure and then the residue was purified by silica gelchromatography (0 to 100% EtOAc in hexanes) to provide the titlecompounds as a viscous orange oil.

Step 2.(R)-6-Chloro-1-(1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine

(Mixture of E/Z of(R))-3,5-Dichloro-2-(1-(2-(1-(2,4-dichlorophenyl)ethyl)hydrazono)-2,2,2-trifluoroethyl)pyrazine(2.5 g, 5.8 mmol) was dissolved in THF (58 mL) and then the solution wascooled to 0° C. Then, 1,8-diazabicyclo[5.4.0]undec-7-ene (1.73 mL, 11.8mmol) was then added dropwise. After the addition was completed, themixture was allowed to warm up to room temperature and stirred for 10 h.The mixture was concentrated under reduced pressure and then the residuewas purified by silica gel chromatography (0 to 20% EtOAc in hexanes) toprovide the title compound as a light orange oil.

General procedure A: Alkylation of tert-butyl3-(piperidin-3-yl)azetidine-1-carboxylate by reductive amination.

Commercialy available tert-butyl3-(piperidin-3-yl)azetidine-1-carboxylate (240 mg, 1 mmol) was dissolvedin 6 mL of dry 1,2-dichloromethane and carbonyl compound (1 mmol) wasadded all at once. Mixture was allowed to stir at room temperature for 5min and then NaBH(OAc)₃ (2 mmol) was added and reaction mixture wasstirred for 1-18 hrs at room temperature. Conversion was monitored byLCMS. Upon completion, saturated sodium bicarbonate solution was addedand the reaction mixture was allowed to stir for additional 30 min. Themixture was extracted 3 times with dichloromethane, combined organicphase was dried over MgSO₄, filtered, and the residue was purified onsilica using methanol dichloromethane as eluent.

General procedure B: Alkylation of tert-butyl3-(piperidin-3-yl)azetidine-1-carboxylate.

tert-Butyl 3-(piperidin-3-yl)azetidine-1-carboxylate (240 mg, 1 mmol)was dissolved in 5 mL of dry solvent and either (a) Michael acceptor (1mmol) was added to the solution all at once and reaction mixture wasstirred either at room temperature or at 50° C. until completeconversion was achieved (followed by LCMS); upon completion solvent wasremoved in vacuo and product purified by silica gel chromatography usingmethanol and dichloromethane as eluent, or (b) 1 mmol of alkyl halide,10 mol % of sodium iodide, and sodium carbonate (2 mmol) were added tothe solution all at once and the reaction mixture was heated to 75° C.under nitrogen atmosphere and monitored by LCMS; upon completion thereaction mixture was diluted with 20 mL of water, extracted 3 times withethyl acetate, combined organic phase was dried over sodium sulfate,filtered, and concentrated under reduced pressure; the residue waspurified on silica using methanol and dichloromethane as the eluent.

General procedure C: Deprotection of 1-alkyl tert-butyl3-(piperidin-3-yl)azetidine-1-carboxylate.

1-Alkyl tert-butyl 3-(piperidin-3-yl)azetidine-1-carboxylate (0.7 mmol)was dissolved in 3 mL of dichloromethane and 2 mL of 4M solution of HClin 1,4-dioxane was added to it. The resulting mixture was stirred atroom temperature until complete conversion was reached (1-3 h). Afterthat solvents were removed in vacuo and residue was dried on high vacuumfor 12 h. Product was used in the next step without purification.

General procedure D: Nucleophilic aromatic substitution with 1-alkyl3-(azetidin-3-yl)piperidine.

1-Alkyl 3-(azetidin-3-yl)piperidine (0.55 mmol) and appropriateheteroaryl precursor I, II, III, IV or V (0.5 mmol) were dissolved in 2mL of dry DMF or DMSO. Diisopropylethylamine (2.5 mmol) was added andmixture was stirred at room temperature (Y═CH, X═N, R²═CN) or at 80° C.(Y═N, X═CH, R²=Me and Y═CH, X═N, R²=Me). Reaction progress was monitoredby LCMS. Upon completion, reaction mixture was either (a) diluted with 2mL of acetonitrile and injected directly on reverse phase HPLC forpurification or (b) concentrated in vacuo, and purified by normal phasesilica gel chromatography using dichloromethane and methanol as eluent.

Precursors VI and VII. Chiral resolution of tert-butyl3-(piperidin-3-yl)azetidine-1-carboxylate

tert-Butyl 3-(3-piperidyl)azetidine-1-carboxylate (77.02 g, 320 mmol)was dissolved in tert-butylmethyl ether (1,700 mL) in a 5-L three-neckedflask equipped with a mechanical stirring and a water condenser. Whenthe mixture was stirred at reflux, L-(+)-mandelic acid (24.38 g, 160mmol) was added. The resulting mixture was allowed to stir at reflux for15 min and then cooled to rt overnight. The white solid was collected byfiltration, rinsing with tert-butylmethyl ether (500 mL). The whitesolid was stirred at reflux in tert-butylmethyl ether (1700 mL) for 30min. The salt was collected by filtration and washed withtert-butylmethyl ether (500 mL). The process was repeated once more toafford a white solid (95% ee).

The white salt (˜62.8g) was further purified by re-crystallization fromchloroform/tert-butylmethyl ether (900 mL/900 mL). The salt wasdissolved in chloroform (900 mL) on a hot plate making it slightlyboiling, then tert-butylmethyl ether (900 mL) was slowly added. It was aclear solution when it was hot. The solution was cooled to ambienttemperature overnight, and crystals appeared. The crystals were isolatedby filtration and further dried under high vacuum for 4 h to afford64.85 g of the mandelate salt with 1 equiv of chloroform by ¹H nuclearmagnetic resonance (“NMR”) in methanol (>99% ee).

Method for % ee determination: Chiral high performance liquidchromatography (“HPLC”), 210 nm, IC-3 column (4.6×250 mm, 3 μM), 50%heptane, 50% isopropanol, 1 mL/min, 210 nM, tert-butyl(R)-3-(piperidin-3-yl)azetidine-1-carboxylate (precursor VI) R_(t)=8.8-9min, tert-butyl (S)-3-(piperidin-3-yl)azetidine-1-carboxylate (precursorVII) R_(t)=8.5 min.

Precursor VIII1-((R)-1-(4-chloro-2-fluorophenyl)ethyl)-6-(34(R)-1-(2-hydroxyethyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrileStep 1: (R)-1-(4-Chloro-2-fluorophenyl)ethan-1-ol

To a solution of 1-(4-chloro-2-fluorophenyl)ethan-1-one (10 g, 58 mmol)in tetrahydrofuran (100 mL) at −78° C. under a nitrogen atmosphere wasadded (+)-B-Chlorodiisopinocampheylborane (50 to 60% wt in hexanes, 9.2mL, 64 mmol), slowly. The resulting mixture was slowly warmed to −25° C.and stirred at this temperature for 2 h.1-(4-Chloro-2-fluorophenyl)ethan-1-one was detected by LCMS (“liquidchromatography mass spectrometry”) and HPLC, and the mixture was cooledback to −78° C. Additional (+)-B-Chlorodiisopinocampheylborane (50 to65% wt in hexanes, 5.4 mL, 38 mmol) was added to the mixture at −78° C.The resulting mixture was slowly warmed to −25° C. and stirred at thistemperature for 5 h. Diethanolamine (18 mL, 191 mmol) was added to thereaction mixture, which was then stirred at room temperature for 3 d.The reaction was filtered, and the filtrate was concentrated andpurified by silica gel chromatography (0 to 30% ethyl acetate inhexanes) to afford 18.8 g impure(R)-1-(chloro-2-fluorophenyl)ethan-1-ol.

Step 2: 4-Chloro-1-(1-chloroethyl)-2-fluorobenzene

To a flask containing (R)-1-(4-chloro-2-fluorophenyl)ethan-1-ol (18.8 g,108 mmol) in dichloromethane (“DCM”) (1 L) was added triphenylphosphine(113 g, 432 mmol) and carbon tetrachloride (41.7 mL, 432 mmol). Themixture was stirred at ambient temperature for 3 d, then silica gel(˜400 g) was added to the mixture. The mixture was then concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (100% hexanes) to afford4-chloro-1-(1-chloroethyl)-2-fluorobenzene (8 g) as a colorless oil.

Step 3: (1-(4-Chloro-2-fluorophenyl)ethyl)hydrazine hydrochloride

To a solution of 4-chloro-1-(1-chloroethyl)-2-fluorobenzene (4.0 g, 41mmol) in ethanol (120 mL) was added hydrazine hydrate (excess). Themixture was stirred at 35° C. for 3 d. The reaction was concentrated,and diethyl was added to the mixture. The bottom hydrazine layer wasremoved, and about 5 mL of 4 M HCl in 1,4-dioxane was added to themixture at 0° C. The mixture was kept at 0° C. until all of thehydrazine HCl salt precipitated. The mixture was filtered, washed withcold diethyl ether, and concentrated in vacuo to afford the titlecompound as the hydrochloride salt (3.95 g), which was used withoutfurther purification.

Step 4.(R)-6-chloro-1-(1-(4-chloro-2-fluorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazine

The title compound was synthesized according to the procedures outlinedin Precursor III, Steps 1-3 and Precursor VI. The crude product waspurified using an alumina column (eluting with 25% to 50% DCM inhexanes) to afford impure6-chloro-1-(1-(4-chloro-2-fluorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazine(2.2 g). This material was repurified by alumina column to afford thetitle compound (1.94 g) as a light yellow oil which was purified by SFC(Lux-amylose 4 (two 2×15 cm columns), eluting with 10% methanol with0.1% DEA and CO2 at 100 bar, 60 mL/min) to afford the pure product as amixture of enantiomers. The enantiomers were separated by preparativechiral SFC (OJ-H (2×25 cm), eluting with 10% isopropanol with 0.1% DEAand CO2 at 100 bar, 70 mL/min) to afford the desired enantiomer as thefirst eluting enantiomer (485 mg) at 2.67 min.

EXEMPLARY COMPOUNDS Example 1

Ethyl2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)acetate2,2,2-trifluoroacetate and 2,2,2-trifluoroacetate ethyl2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)acetate.Prepared as a mixture of the above two diastereomers using generalprocedure A with 50% toluene solution of ethyl 2-oxoacetate, followed byprocedure C. The resulting diasteromeric mixture product was condensedwith Precursor II using procedure D (a). ¹H NMR (400 MHz, CDCl₃,trifluoroacetic acid salt): δ ppm 10.43 (bs, 1H), 7.66 (s, 1H),7.37-7.39 (m, 2H), 7.12-7.17 (m, 1H), 6.26-6.35 (m, 1H), 4.16-4.29 (m,4H), 3.88-3.96 (m, 4H), 3.54-3.68 (m, 2H), 3.07-3.20 (m, 1H), 2.80-2.94(m, 1H), 2.54-2.68 (m, 4H), 2.30-2.43 (m, 1H), 1.92-2.10 (m, 3H), 1.88(d, J=7.1 Hz, 3H), 1.29 (t, J=7.1 Hz, 3H), 1.08-1.23 (m, 1H). [M+H]531.3.

Example 2

2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)aceticacid. The diastereomers of Example 1 were separated using 5% isopropanolin heptanes (0.1% diethylamine) on CHIRALPAK IF SFC 20×250 mm (5 μM),followed by treatment of the first eluting diastereomer with 5 equiv ofLiOH in MeOH at room temperature for 12 hrs, and repurifying by reversephase HPLC using water (0.1% TFA) and acetonitrile (0.1% TFA) as eluent.¹H NMR (400 MHz, CDCl₃, trifluoroacetic acid salt): δ ppm 7.68 (m, 1H),7.35-7.40 (m, 1H), 7.31-7.33 (m, 1H), 7.12-7.16 (m, 1H), 6.29 (q, J=7.0Hz, 1H), 4.16-4.26 (m, 2H), 3.86-3.98 (m, 4H), 3.64-3.78 (m, 2H),2.75-2.88 (m, 1H), 2.48-2.65 (m, 5H), 2.28-2.41 (m, 1H), 1.84-2.10 (m,6H), 1.00-1.18 (m, 1H); [M+H] 503.3.

Example 3

2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)aceticacid. The diastereomers of Example 1 were separated at the ester stageusing 5% isopropanol in heptanes (0.1% diethylamine) on CHIRALPAK IF SFC20×250 mm (5 followed by treatment of the second eluting diastereomerwith 5 equiv of LiOH in MeOH at room temperature for 12 h, andrepurifying by reverse phase HPLC using water (0.1% TFA) andacetonitrile (0.1% TFA) as eluent. ¹H NMR (400 MHz, CDCl₃,trifluoroacetic acid salt): δ ppm 11.42 (bs, 2H), 7.68 (s, 1H),7.36-7.40 (m, 1H), 7.32-7.34 (m, 1H), 7.12-716 (m, 1H), 6.31 (q, J=7.0Hz, 1H), 4.18-4.26 (m, 2H), 3.85-3.98 (m, 4H), 3.65-3.78 (m, 2H),2.74-2.88 (m, 1H), 2.48-2.60 (m, 5H), 2.28-2.40 (m, 1H), 1.85-2.08 (m,6H), 1.00-1.15 (m, 1H). [M+H] 503.3.

Example 4

2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethane-1-sulfonamideand2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethane-1-sulfonamide.Prepared as a mixture of the above two diastereomers using generalprocedure B (a) with ethenesulfonyl fluoride and treating resultingmixture with aqueous ammonia at 70° C. for 30 min followed by procedureC and the resulting diasteromeric mixture product was condensed withPrecursor II using procedure D (a). [M+H] 552.2.

Example 5

2-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-ypethane-1-sulfonamide.The diastereomers of example 4 were separated using 45% isopropanol inheptanes (0.1% diethylamine) on CHIRALPAK IF SFC 20×250 mm (5 The firsteluting diastereomer had the structure indicated above. ¹H NMR (400 MHz,CD₃OD, trifluoroacetic acid salt): δ ppm 7.71 (s, 1H), 7.29-7.44 (m,1H), 7.35-7.39 (m, 1H), 7.23-7.27 (m, 1H), 6.28 (q, J=7.1 Hz, 1H), 4.21(dt, J=2.6 Hz, J=8.5 Hz, 2H), 3.89-3.95 (m, 2H), 3.28-3.33 (m, 1H),2.83-2.94 (m, 4H), 2.52-2.64 (m, 1H), 2.49 (s, 3H), 2.03-2.13 (m, 1H),1.72-1.89 (m, 7H), 1.52-1.65 (m, 1H), 1.15 (d, J=6.2 Hz, 3H), 0.88-1.02(m, 1H). [M+H] 552.2.

Example 6

2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethane-1-sulfonamide.The diastereomers of example 4 were separated using 45% isopropanol inheptanes (0.1% diethylamine) on CHIRALPAK IF SFC 20×250 mm (5 The secondeluting diastereomer had the structure indicated above. ¹H NMR (400 MHz,CD₃OD, trifluoroacetic acid salt): δ ppm 7.71 (s, 1H), 7.42-7.45 (m,1H), 7.35-7.39 (m, 1H), 7.23-7.27 (m, 1H), 6.28 (q, J=7.0 Hz, 1H), 4.21(dt,=5.6 Hz,=8.4 Hz, 2H) ppm 3.91 (dt, J=5.9 Hz, J=9.4 Hz, 2H),3.27-3.33 (m, 1H), 2.83-2.94 (m, 4H), 2.53-2.63 (m, 1H), 2.49 (s, 3H),2.02-2.12 (m, 1H), 1.70-1.90 (m, 7H), 1.52-1.64 (m, 1H), 1.15 (d, J=6.2Hz, 1H), 0.87-1.00 (m, 1H). [M+H] 552.3.

Example 7

3-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propanoicacid and3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propanoicacid. Prepared as a mixture of the above two diastereomers using generalprocedure B (a) with methyl acrylate, followed by procedure C and theresulting diasteromeric mixture product was condensed with Precursor IIusing procedure D (a), followed by treatment of the diastereomericmixture with 5 equiv of LiOH in MeOH at room temperature for 12 h, andrepurifying by reverse phase HPLC using water (0.1% TFA) andacetonitrile (0.1% TFA) as eluent. [M+H] 517.3.

Example 8

3-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propanoicacid. The example was prepared using general procedure B (a) with methylacrylate, followed by procedure C and the resulting product wascondensed with

Precursor II using procedure D (a), followed by treatment of thediastereomeric mixture with 5 equiv of LiOH in MeOH at room temperaturefor 12 h, and purifying by reverse phase HPLC using water (0.1% TFA) andacetonitrile (0.1% TFA) as the eluent. Diastereomers were separatedusing 40% isopropanol (0.1% diethylamine) and 100 bar CO₂ on AD-H SFC20×250 mm (5 μM). The first eluting diastereomer had the structureindicated above. ¹H NMR (400 MHz, CD₃OD, trifluoroacetic acid salt): δppm 7.74 (s, 1H), 7.44-7.46 (m, 1H), 7.34-7.38 (m, 1H), 7.24-7.28 (m,1H), 6.29 (q, J=7.1 Hz, 1H), 4.21-4.31 (m, 2H), 3.98-4.01 (m, 2H),3.33-3.43 (m, 2H), 3.11-3.19 (m, 2H), 2.62-2.75 (m, 2H), 2.54 (t, J=6.9Hz, 2H), 2.42-2.52 (m, 4H), 1.68-2.12(m, 7H), 1.10-1.23 (m, 1H). [M+H]517.3.

Example 9

3-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propanoicacid. The example was prepared using general procedure B (a) with methylacrylate, followed by procedure C and the resulting product wascondensed with Precursor II using procedure D (a), followed by treatmentof the diastereomeric mixture with 5 equiv of LiOH in MeOH at roomtemperature for 12 h, and purifying by reverse phase HPLC using water(0.1% TFA) and acetonitrile (0.1% TFA) as eluent. Diastereomers wereseparated using 40% isopropanol (0.1% diethylamine) and 100 bar CO₂ onAD-H SFC 20×250 mm (5 μM). The second eluting diastereomer had thestructure indicated above. ¹H NMR (400 MHz, CD₃OD, trifluoroacetic acidsalt): δ ppm 7.73 (s, 1H), 7.43-7.45 (m, 1H), 7.34-7.38 (m, 1H),7.23-7.28 (m, 1H), 6.28 (q, J=7.1 Hz, 1H), 4.22-4.29 (m, 2H), 3.93-4.01(m, 2H), 3.30-3.40 (m, 2H), 3.10-3.17 (m, 2H), 2.62-2.72 (m, 2H),2.50-2.56 (m, 2H), 2.50 (s, 3H), 2.36-2.50 (m, 1H), 1.99-2.10 (m, 1H),1.84-1.99 (m, 5H), 1.68-1.80 (m, 1H), 1.09-1.22 (m, 1H). [M+H] 517.3.

Example 10

4-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoicacid. The example was prepared using general procedure A with methyl4-oxobutanoate, followed by procedure C and the resulting product wascondensed with Precursor II using procedure D (a). Diastereomers wereseparated at the ester stage using 25% ethanol in heptanes (0.1%diethylamine) on CHIRACEL OZ-H 20×250 mm (5 μM), followed by treatmentof the first eluting diastereomer with 5 equiv of LiOH in MeOH at roomtemperature for 12 h, and purifying by reverse phase HPLC using water(0.1% TFA) and acetonitrile (0.1% TFA) as eluent. ¹H NMR (400 MHz,ACN-d3, trifluoroacetic acid salt): δ ppm 8.03 (bs, 1H), 7.73 (s, 1H),7.46-7.48 (m, 1H), 7.39-7.43 (m, 1H), 7.24-7.28 (m, 1H), 6.25 (q, J=7.1Hz, 1H), 4.14-4.24 (m, 2H), 3.86-3.94 (m, 2H), 3.44-3.58 (m, 2H),3.04-3.12 (m, 2H), 2.73-2.85 (m, 1H), 2.48-2.65 (m, 2H), 2.41-2.47 (m,5H), 1.68-2.16 (m, 8H), 1.06-1.20 (m, 1H). [M+H] 531.2.

Example 11

4-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoicacid. Prepared using general procedure A with methyl 4-oxobutanoate,followed by procedure C and the resulting product was condensed withPrecursor II using procedure D (a). Diastereomers were separated at theester stage using 25% ethanol in heptanes (0.1% diethylamine) onCHIRACEL OZ-H 20×250 mm (5μ), followed by treatment of the secondeluting diastereomer with 5 eq of LiOH in MeOH at room temperature for12 hrs, and repurifying by reverse phase HPLC using water (0.1% TFA) andacetonitrile (0.1% TFA) as eluent. ¹H NMR (400 MHz, ACN-d3,trifluoroacetic acid salt): δ ppm 8.27 (bs, 1H), 7.73 (s, 1H), 7.46-7.48(m, 1H), 7.40-7.44 (m, 1H), 7.24-7.28 (m, 1H), 6.24 (q, J=7.1 Hz, 1H),4.15-4.23 (m, 2H), 3.85-3.95 (m, 2H), 3.43-3.58 (m, 2H), 3.03-3.13 (m,2H), 2.72-2.84 (m, 1H), 2.47-2.65 (m, 2H), 2.41-2.46 (m, 5H), 2.05-2.18(m, 1H), 1.92-2.02 (m, 3H), 1.69-1.92 (m, 5H), 1.06-1.19 (m, 1H). [M+H]531.2.

Example 12

3-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propanamide.Prepared using general procedure B (a) using acrylamide, followed byprocedure C and the resulting product was condensed with Precursor IIusing procedure D (a). Diastereomers were separated using 20% ethanol inheptanes (0.1% diethylamine) on CHIRALPAK ID 20×250 mm (5 μM). The firsteluting diastereomer had the structure indicated above. ¹H NMR (400 MHz,CDCl₃, free base): δ ppm 8.08 (bs, 1H), 7.64 (s, 1H), 7.35-7.38 (m, 1H),7.32-7.35 (m, 1H), 7.10-7.15 (m, 1H), 6.30 (q, J=7.1 Hz, 1H), 5.80 (bs,1H), 4.14-4.22 (m, 2H), 3.83-3.90 (m, 2H), 2.85-2.98 (m, 2H), 2.63-2.72(m, 2H), 2.52-2.62 (m, 4H), 2.40-2.48 (m, 2H), 2.00-2.10 (m, 1H),1.73-1.91 (m, 7H), 1.52-1.64 (m, 1H), 0.90-1.14 (m, 1H). [M+H] 516.3.

Example 13

3-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propanamide.The example was prepared using general procedure B (a) using acrylamide,followed by procedure C and the resulting product was condensed withPrecursor II using procedure D (a). Diastereomers were separated using20% ethanol in heptanes (0.1% diethylamine) on CHIRALPAK ID 20×250 mm (5μM). The second eluting diastereomer had the structure indicated above.¹H NMR (400 MHz, CDCl₃, free base): δ ppm 8.09 (bs, 1H), 7.64 (s, 1H),7.35-7.39 (m, 1H), 7.33-7.35 (m, 1H), 7.11-7.15 (m, 1H), 6.31 (q, J=7.1Hz, 1H), 5.54 (bs, 1H), 4.15-4.24 (m, 2H), 3.82-3.90 (m, 2H), 2.83-2.96(m, 2H), 2.60-2.66 (m, 2H), 2.55-2.60 (m, 4H), 2.40-2.46 (m, 2H),1.97-2.07 (m, 1H), 1.70-1.90 (m, 7H), 1.50-1.63 (m, 1H), 0.90-1.03 (m,1H). [M+H] 516.3.

Example 14

3-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propan-1-ol.The example was prepared using general procedure A with methyl4-oxobutanoate, followed by reduction of ester with 5 equiv of LiBH4 inTHF/MeOH at room temperature, and then applying general procedure C andthe resulting product was coupled with Precursor II using procedure D(a). Diastereomers were separated using 20% ethanol in heptanes (0.1%diethylamine) on CHIRACEL OZ-H 20×250 mm (5 μM). The first elutingdiastereomer had the structure indicated above. ¹H NMR (400 MHz, CDCl₃,free base): δ ppm 7.64 (s, 1H), 7.36-7.40 (m, 1H), 7.33-7.36 (m, 1H),7.12-7.16 (m, 1H), 6.31 (q, J=7.1 Hz, 1H), 4.15-4.23 (m, 2H), 3.88-3.94(m, 1H), 3.83-3.88 (m, 1H), 3.77-3.82 (m, 2H), 2.92-3.06 (m, 2H),2.53-2.65 (m, 6H), 1.50-2.06 (m, 11H), 0.88-1.02 (m, 1H). [M+H] 503.0.

Example 15

3-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propan-1-ol.The example was prepared using general procedure A with methyl4-oxobutanoate, followed by reduction of ester with 5 equiv of LiBH₄ inTHF/MeOH at room temperature, and then applying general procedures C andthe resulting product was coupled with Precursor II using procedure D(a). Diastereomers were separated using 20% ethanol in heptanes (0.1%diethylamine) on CHIRACEL OZ-H 20×250 mm (5 μM). The second elutingdiastereomer had the structure indicated above. ¹H NMR (400 MHz, CDCl₃,free base): δ ppm 7.63 (s, 1H), 7.34-7.39 (m, 2H), 7.11-7.15 (m, 1H),6.30 (q, J=7.1 Hz, 1H), 4.14-4.22 (m, 2H), 3.84-3.94 (m, 2H), 3.77-3.82(m, 2H), 2.89-3.03 (m, 2H), 2.52-2.64 (m, 6H), 1.65-2.05 (m, 10H),1.49-1.63 (m, 1H), 0.88-1.02 (m, 1H). [M+H] 503.0.

Example 16

Cis-3-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)cyclobutane-1-carboxylicacid;trans-3-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)cyclobutane-1-carboxylicacid;Cis-3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)cyclobutane-1-carboxylicacid; andtrans-3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)cyclobutane-1-carboxylicacid. Prepared as a mixture of the above four diastereomers usinggeneral procedure A using 3-oxocyclobutane-1-carboxylic acid, followedby procedure C and the resulting diasteromeric mixture product wascoupled with Precursor II using procedure D(a). [M+H] 543.2.

Example 17

4-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoicacid and 4-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoicacid. Prepared as a mixture of the above two diastereomers using generalprocedure A with methyl 4-oxobutanoate, followed by procedure C and theresulting diasteromeric mixture product was coupled with Precursor IIusing procedure D (a), followed by treating diastereomeric mixture with5 equiv of LiOH in MeOH at room temperature for 12 h, and purifying byreverse phase HPLC using water (0.1% TFA) and acetonitrile (0.1% TFA) asthe eluent. [M+H] 542.2.

Example 18

4-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoicacid. The disatereomers from example 17 were separated on AD-H 20×250 mmcolumn using 40% isopropanol (0.1% diethylamine) and 100 bar CO₂. Thefirst eluting disastereomer had the structure indicated above. ¹H NMR(400 MHz, CDCl₃, free base): δ ppm 7.82 (s, 1H), 6.34-7.38 (m, 2H),7.17-7.21 (m, 1H), 6.45 (q, J=7.1 Hz, 1H), 4.20-4.30 (m, 2H), 3.88-4.00(m, 2H), 3.02-3.14 (m, 2H), 2.57-2.70 (m, 3H), 2.45-2.55 (m, 2H),2.18-2.30 (m, 1H), 1.68-2.10 (m, 10H), 0.93-1.07 (m, 1H). [M+H] 542.2.

Example 19

4-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoicacid and4-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoicacid. The example was prepared using general procedure A with methyl4-oxobutanoate, C and D (a), followed by treating diastereomeric mixturewith 5 equiv of LiOH in MeOH at room temperature for 12 h, and purifyingby reverse phase HPLC using water (0.1% TFA) and acetonitrile (0.1% TFA)as eluent. Disatereomers were separated on AD-H 20×250 mm column using40% isopropanol (0.1% diethylamine) and 100 bar CO₂. The second elutingdiastereomer had the structure indicated above. ¹H NMR (400 MHz, CDCl₃,free base): δ ppm 7.82 (s, 1H), 7.34-7.38 (m, 2H), 7.17-7.21 (m, 1H),6.44 (q, J=7.1 Hz, 1H), 4.19-4.29 (m, 2H), 3.90-4.02 (m, 2H), 3.04-3.16(m, 2H), 2.48-2.74 (m, 5H), 2.23-2.33 (m, 1H), 1.95-2.20 (m, 2H),1.70-1.91 (m, 8H), 0.96-1.09 (m, 1H). [M+H] 542.2.

Example 20

4-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoicacid and4-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoicacid. Prepared as a mixture of the above two diastereomers using generalprocedure A with methyl 4-oxobutanoate, followed by procedure C and theresulting diasteromeric mixture product was condensed with Precursor Iusing procedure D (a), followed by treating the diastereomeric mixturewith 5 equiv of LiOH in MeOH at room temperature for 12 h, and purifiedby reverse phase HPLC using water (0.1% TFA) and acetonitrile (0.1% TFA)as eluent. [M+H] 531.3.

Example 21

4-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoicacid. The example was prepared using general procedure A with methyl4-oxobutanoate, followed by procedure C and condensing the product withPrecursor I using procedure D (a), followed by treating diastereomericmixture with 5 equiv of LiOH in MeOH at room temperature for 12 h, andpurifying by reverse phase HPLC using water (0.1% TFA) and acetonitrile(0.1% TFA) as eluent. Diastereomers were separated on AD-H 20×250 mmcolumn using 30% ethanol (0.1% diethylamine) and 100 bar CO₂. The firsteluting diastereomer had the structure indicated above. ¹H NMR (400 MHz,CDCl₃, free base): δ ppm 8.61 (s, 1H), 7.39-7.43 (m, 1H), 7.33-7.36 (m,1H), 7.13-7.17 (m, 1H), 6.29 (q, J=7.1 Hz, 1H), 4.12-4,23 (m, 2H),3.82-3.94 (m, 2H), 3.06-3.21 (m, 2H), 2.66-2.76 (m, 2H), 2.53-2.63 (m,2H), 2.42-2.52 (m, 4H), 2.22-2.35 (m, 1H), 1.95-22.10 (m, 2H), 1.75-1.94(m, 7H), 1.22-1.32 (m, 1H), 0.94-1.06 (m, 1H). [M+H] 531.3.

Example 22

4-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoicacid. The example was prepared using general procedure A with methyl4-oxobutanoate, followed by procedure C and condensing the product withPrecursor I using procedure D (a), followed by treating thediastereomeric mixture with 5 equiv of LiOH in MeOH at room temperaturefor 12 h, and purifying by reverse phase HPLC using water (0.1% TFA) andacetonitrile (0.1% TFA) as the eluent. Diastereomers were separated onAD-H 20×250 mm column using 30% ethanol (0.1% diethylamine) and 100 barCO₂. The structure was assigned to the second eluting diastereomer. ¹HNMR (400 MHz, CDCl₃, free base): δ ppm 8.61 (s, 1H), 7.40-7.44 (m, 1H),7.34-7.36 (m, 1H), 7.13-7.17 (m, 1H), 6.28 (q, J=7.1 Hz, 1H), 4.13-4.23(m, 2H), 3.85-3.93 (m, 2H), 3.03-3.17 (m, 2H), 2.65-2.76 (m, 2H),2.57-2.62 (m, 2H), 2.45-2.55 (m, 4H), 2.21-2.32 (m, 1H), 1.94-2.10 (m,2H), 1.73-1.92 (m, 8H), 0.95-1.18 (m, 1H). [M+H] 531.3.

Example 23

1-((R)-1-(2,4-Dichlorophenyl)ethyl)-6-(3-((S)-1-(2-(methylsulfonyl)ethyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrileand1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-(2-(methylsulfonyl)ethyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.Prepared as a mixture of the above two diastereomers using generalprocedure B (a) with methylvinyl sulfone, prodeedure C and condensationof the resulting diasteromeric mixture product with Precursor IV usingprocedure D (a). ¹H NMR (400 MHz, CDCl₃; trifluoroacetic acid salt): δppm 9.76 (bs, 1H), 7.85 (s, 1H), 7.39-7.34 (m, 2H), 7.20 (dd, J=8.5, 2.1Hz, 1H), 6.45 (qd, J=7.0, 3.2 Hz, 1H), 4.35-4.23 (m, 2H), 4.06-3.94 (m,2H), 3.78-3.52 (m, 5H), 3.04 (s, 3H), 2.92-2.78 (m, 1H), 2.74-2.59 (m,1H), 2.60-2.47 (m, 1H), 2.36-2.21 (m, 1H), 2.14-1.93 (m, 4H), 1.90 (d,J=7.1 Hz, 3H), 1.28-1.11 (m, 1H). [M+H] 562.0.

Example 24

3-((S)-3-(1-(3-Cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propanamideand3-((R)-3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propanamide.Prepared as a mixture of the above two diastereomers using generalprocedure B (a) using acrylamide, followed by procedure C andcondensation of the resulting diasteromeric mixture product withPrecursor IV using procedure D (a). [M+H] 527.2.

Example 25

3-((S)-3-(1-(3-Cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propanamide.The diastereomers prepared in Example 24 were separated on an AD-H20×250 mm column using 30% ethanol (0.1% diethylamine) and 100 bar CO₂.The first eluting isomer was assigned the structure. ¹H NMR (400 MHz,DMSO-d6, free base): δ ppm 8.04 (s, 1H), 7.64-7.66 (m, 1H), 7.41-7.49(m, 2H), 7.36 (bs, 1H), 7.76 (bs, 1H), 6.32 (q, J=7.0 Hz, 1H), 4.08-4.36(bm, 2H), 3.30-4.08 (bm, 2H), 2.67-2.75 (m, 2H), 2.54-2.64 (m, 1H),2.43-2.53 (m, 2H), 2.17-2.24 (m, 2H), 1.80.1-96 (m, 4H), 1.56-1.80 (m,4H), 1.34-1.48 (m, 1H), 0.78-0.92 (m, 1H). [M+H] 527.2.

Example 26

3-((R)-3-(1-(3-Cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propanamide.The diastereomers prepared in Example 24 were separated on an AD-H20×250 mm column using 30% ethanol (0.1% diethylamine) and 100 bar CO₂.The second eluting isomer was assigned the structure indicated above. ¹HNMR (400 MHz, DMSO-d6, free base): δ ppm 8.05 (s, 1H), 7.65-7.67 (m,1H), 7.41-7.48 (m, 2H), 7.36 (bs, 1H), 6.76 (bs, 1H), 6.32 (q, J=7.1 Hz,1H), 4.06-4.36 (bm, 2H), 3.80-4.06 (bm, 2H), 2.67-2.77 (m, 2H),2.52-2.63 (m, 1H), 2.46-2.53 (m, 2H), 2.17-2.23 (m, 2H), 1.82-1.95 (m,4H), 1.57-1.79 (m, 4H), 1.35-1.49 (m, 1H), 0.78-0.92 (m, 1H). [M+H]527.2.

Example 27

1-((R)-1-(2,4-Dichlorophenyl)ethyl)-6-(3-((S)-1-((S)-2-hydroxypropyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile;1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((S)-1-((R)-2-hydroxypropyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile;1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-((S)-2-hydroxypropyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile ; and1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-((R)-2-hydroxypropyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.Prepared as a mixture of the above four diastereomers using generalprocedure A hydroxyacetone, followed by procedure C, and condensation ofthe resulting diasteromeric mixture product with Precursor IV usingprocedure D (a). LCMS: [M+H] 514.3. The diasteremers separated on AD-H20×250 mm column using 40% isopropanol (0.2% n-propylamine) and 100 barCO₂.

Example 28

First eluting isomer of Example 27 mixture. ¹H NMR (400 MHz, CDCl₃, freebase): δ ppm 7.82 (s, 1H), 7.33-7.43 (bm, 2H), 7.16-7.23 (m, 1H),6.40-6.50 (bq, 1H), 4.18-4.30 (m, 2H), 3.87-3.97 (m, 2H), 3.24-3.45 (m,2H), 2.46-2.90 (m, 5H), 1.50-1.96 (m, 10H), 0.85-1.04 (2H). [M+H] 514.3.

Example 29

Second eluting isomer of Example 27 mixture. ¹H NMR (400 MHz, CD₃OD,trifluoroacetic acid salt): δ ppm 7.96 (s, 1H), 7.47-7.49 (m, 1H),7.29-7.38 (m, 2H), 6.45 (q, J=7.1 Hz, 1H), 4.28-4.38 (m, 2H), 3.96-4.10(m, 2H), 3.84-3.90 (m, 1H), 3.66-3.74 (m, 1H), 3.38-3.59 (m, 3H),3.95-4.05 (m, 1H), 2.82-2.92 (m, 1H), 2.64-2.76 (m, 1H), 2.15-2.29 (m,1H), 2.74-2.10 (m, 6H), 1.33 (d, J=6.8 Hz, 3H), 1.15-1.28 (m, 1H). [M+H]514.3.

Example 30

Third eluting isomer of Example 27 mixture. ¹H NMR (400 MHz, CD₃OD,trifluoroacetic acid salt): δ ppm 7.97 (s, 1H), 7.48-7.50 (m, 1H),7.35-7.39 (m, 1H), 7.30-7.34 (m, 1H), 6.46 (q, J=7.1 Hz, 1H), 4.27-4.39(m, 2H), 3.98-4.08 (m, 2H), 3.85-3.92 (m, 1H), 3.69-3.76 (m, 1H),3.43-3.51 (m, 3H), 3.07-3.18 (m, 1H), 2.74-2.84 (m, 1H), 2.65-2.74 (m,1H), 1.82-2.20 (m, 7H), 1.35 (d, J=6.8 Hz, 3H), 1.15-1.28 (m, 1H). [M+H]514.3.

Example 31

Fourth eluting isomer of Example 27 mixture. ¹H NMR (400 MHz, CD₃OD,trifluoroacetic acid salt): δ ppm 7.96 (s, 1H), 7.46-7.48 (m, 1H),7.34-7.39 (m, 1H), 7.29-7.33 (m, 1H), 6.45 (q, J=7.0 Hz, 1H), 4.26-4.38(m, 2H), 4.00-4.08 (m, 2H), 3.84-3.90 (m, 1H), 3.66-3.73 (m, 1H),3.39-3.59 (m, 3H), 2.95-3.05 (m, 1H), 2.82-2.92 (m, 1H), 2.65-2.75 (m,1H), 2.16-2.28 (m, 1H), 1.75-2.10 (m, 6H), 1.34 (d, J=6.8 Hz, 3H),1.14-1.27 (m, 1H). [M+H] 514.3.

Example 32

4-((S)-3-(1-(3-Carbamoyl-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoicacid. The example was prepared using general procedure A with methyl4-oxobutanoate, then applying procedure C and condensing the productwith precursor III using procedure D (a). Diastereomers were separatedat the ester stage on OJ-H 20×250 mm column using 25% ethanol (0.1%diethylamine) and 100 bar CO₂, followed by treating the first elutingpeak with 5 equiv of LiOH in MeOH at room temperature for 12 h, andrepurifying by reverse phase HPLC using water (0.1% TFA) andacetonitrile (0.1% TFA) as the eluent. ¹H NMR (400 MHz, CD₃OD,trifluoroacetic acid salt): δ ppm 7.74 (s, 1H), 7.43-7.45 (m, 1H),7.38-7.42 (m, 1H), 7.23-7.28 (m, 1H), 6.41 (q, J=7.1 Hz, 1H), 4.19-4.29(m, 2H), 3.90-4.00 (m, 2H), 3.54-3.68 (m, 2H), 3.17-3.24 (m, 2H),2.86-2.96 (m, 1H), 2.60-2.73 (m, 2H), 2.44-2.50 (m, 2H), 1.76-2.22 (m,9H), 1.14-1.27 (m, 1H). [M+H] 560.2.

Example 33

4-((R)-3-(1-(3-Carbamoyl-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoicacid. The example was prepared using general procedure A with methyl4-oxobutanoate, C and D (a). Diastereomers were separated at the esterstage on OJ-H 20×250 mm column using 25% ethanol (0.1% diethylamine) and100 bar CO₂, followed by treating the second eluting peak with 5 equivof LiOH in MeOH at room temperature for 12 h and repurifying by reversephase HPLC using water (0.1% TFA) and acetonitrile (0.1% TFA) as theeluent. ¹H NMR (400 MHz, CD₃OD, trifluoroacetic acid salt): δ ppm 7.80(s, 1H), 7.44-7.46 (m, 1H), 7.39-7.43 (m, 1H), 7.24-7.28 (m, 1H), 6.43(q, J=7.0 Hz, 1H), 4.21-4.32 (m, 2H), 3.94-4.02 (m, 2H), 3.54-3.68 (m,2H), 3.16-3.25 (m, 2H), 2.86-2.96 (m, 1H), 2.61-2.73 (m, 2H), 2.44-2.50(m, 2H), 1.77-2.20 (m, 9H), 1.14-1.28 (m, 1H). [M+H] 560.2.

Example 34

1-((R)-1-(2,4-Dichlorophenyl)ethyl)-6-(3-((S)-1-(2-hydroxyethyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrileand1-((S)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((S)-1-(2-hydroxyethyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.Prepared as a mixture of the above two diastereomers using generalprocedure A with 2-((tert-butyldimethylsilyl)oxy)acetaldehyde, followedby procedure C and condensing the resulting diasteromeric mixtureproduct with Precursor IV using procedure D (b). [M+H] 500.3.

Example 35

1-((R)-1-(2,4-Dichlorophenyl)ethyl)-6-(3-((S)-1-(2-hydroxyethyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrileThe diastereomers prepared in Example 34 were separated on CHIRALPAK IFSFC 210×50 mm column using 40% ethanol (0.1% diethylamine) in heptanes.The first eluting isomer had the structure indicated above. ¹H NMR (400MHz, CD₃OD, HCl salt): δ ppm 7.93 (s, 1H), 7.51-7.53 (m, 1H), 7.41-7.45(m, 1H), 7.31-7.35 (m, 1H), 6.42 (q, J=7.1 Hz, 1H), 4.19-4.33 (m, 2H),3.97-4.07 (m, 2H), 3.86-3.91 (m, 2H), 3.51-3.64 (m, 2H), 3.11-3.17 (m,2H), 2.90-3.00 (m, 2H), 2.72-2.84 (m, 1H), 2.58-2.68 (m, 1H), 2.48-2.56(m, 2H), 2.05-2.40 (m, 2H), 1.88-1.93 (m, 3H), 1.08-1.20 (m, 1H). [M+H]500.3.

Example 36

1-((S)-1-(2,4-Dichlorophenyl)ethyl)-6-(3-((S)-1-(2-hydroxyethyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrileThe diastereomers prepared in example 34 were separated on CHIRALPAK IFSFC 210×50 mm column using 40% ethanol (0.1% diethylamine) in heptanes.The second eluting isomer had the structure indicated above. ¹H NMR (400MHz, CD₃OD, free base): δ ppm 7.92 (s, 1H), 7.43-7.46 (m, 1H), 7.33-7.38(m, 1H), 7.26-.732 (m, 1H), 6.43 (q, J=6.9 Hz, 1H), 4.27-4.37 (m, 2H),3.98-4.09 (m, 2H), 3.88-3.94 (m, 2H), 3.57-3.70 (m, 2H), 3.24-3.30 (m,2H), 2.90-3.00 (m, 1H), 2.65-2.78 (m, 2H), 2.13-2.26 (m, 1H), 1.80-2.08(m, 6H), 1.15-1.28 (m, 1H). [M+H] 500.3.

Example 37

2-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-oland 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol.Prepared as a mixture of the above two diastereomers using generalprocedure A with 2-((tert-butyldimethylsilyl)oxy)acetaldehyde, followedby procedure C and condensation of the resulting diasteromeric mixtureproduct with Precursor I using procedure D (b). [M+H] 489.1.

Example 38

2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol. Thediastereomers prepared in Example 37 were separated on AD-H 20×250 mmcolumn using 25% ethanol (0.1% diethylamine) and 100 bar CO₂. The firsteluting diastereomer had the structure indicated above. ¹H NMR (400 MHz,CDCl₃, free base): δ ppm 8.61 (s, 1H), 7.40-7.44 (m, 1H), 7.34-7.36 (m,1H), 7.13-7.17 (m, 1H), 6.30 (q, J=7.1 Hz, 1H), 4.13-4.23 (m, 1H),3.82-3.92 (m, 2H), 3.61-3.66 (m, 2H), 2.85-2.95 (m, 2H), 2.54-2.60 (m,2H), 2.42-2.52 (m, 4H), 2.04-2.14 (m, 1H), 1.55-1.94 (m, 9H), 0.87-1.00(m, 1H). [M+H] 489.1.

Example 39

2-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol.The diastereomers prepared in Example 37 were separated on AD-H 20×250mm column using 25% ethanol (0.1% diethylamine) and 100 bar CO₂. Thesecond eluting diastereomer had the structure indicated above. ¹H NMR(400 MHz, CDCl₃, free base): δ ppm 8.61 (s, 1H), 7.41-7.45 (m, 1H),7.35-7.37 (m, 1H), 7.13-7.17 (m, 1H), 6.29 (q, J=7.1 Hz, 1H), 4.14-4.22(m, 2H), 3.84-3.92 (m, 2H), 3.58-3.63 (m, 2H), 2.79-2.89 (m, 2H),2.43-2.56 (m, 6H), 2.00-2.10 (m, 2H), 1.68-1.88 (m, 8H), 1.50-1.63 (m,1H), 0.86-1.00 (m, 1H). [M+H] 489.1.

Example 40

2-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-oland2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol.Prepared as a mixture of the above two diastereomers using generalprocedure A with 2-((tert-butyldimethylsilyl)oxy)acetaldehyde, followedby procedure C and condensation of the resulting diasteromeric mixtureproduct with Precursor II using procedure D (b). [M+H] 489.3.

Example 41

1-((R)-1-(2,4-Dichlorophenyl)ethyl)-6-(3-((S)-1-(2-hydroxyethyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carboxamideand1-((S)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((S)-1-(2-hydroxyethyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carboxamide. Prepared as a mixture of the above twodiastereomers using general procedure A with2-((tert-butyldimethylsilyl)oxy)acetaldehyde, followed by procedure Cand condensation of the resulting diasteromeric mixture product withPrecursor III using procedure D (b). [M+H] 518.3.

Example 42

2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-oland2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol.Prepared as a mixture of the above two diastereomers using generalprocedure A with 2-((tert-butyldimethylsilyl)oxy)acetaldehyde, followedby procedure C and condensation of the resulting diasteromeric mixtureproduct with Precursor V using procedure D (b). LCMS [M+H]: 543.0.

Example 43

2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol.The diastereomers prepared in Example 42 were separated on CHIRACEL IFcolumn using 5% ethanol and heptanes (0.1% diethylamine). The firsteluting diastereomer had the structure indicated above. ¹H NMR (400 MHz,CDCl₃, free base): δ ppm 7.83 (s, 1H), 7.38 (d, J=2.3 Hz, 1H), 7.37 (d,J=8.7 Hz, 1H), 7.19 (dd, J=8.5, 2.1 Hz, 1H), 6.46 (q, J=7.0 Hz, 1H),4.24 (q, J=8.8 Hz, 2H), 3.97-3.86 (m, 2H), 3.62 (t, J=5.4 Hz, 2H), 2.84(t, J=9.9 Hz, 2H), 2.68-2.59 (m, 1H), 2.56-2.52 (m, 2H), 2.08 (t, J=10.3Hz, 1H), 1.93 (d, J =7.1 Hz, 3H), 1.88-1.70 (m, 4H), 1.63-1.53 (m, 1H),1.01-0.92 (m, 1H). LCMS [M+H]: 543.0.

Example 44

2-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol.The diastereomers prepared in Example 42 were separated on CHIRACEL IFcolumn using 5% ethanol and heptanes (0.1% diethylamine). The secondeluting diastereomer had the structure indicated above. 1H NMR (400 MHz,CDCl₃; free base) δ 7.83 (s, 1H), 7.39 (d, J=2.1 Hz, 1H), 7.36 (d, J=8.5Hz, 1H), 7.19 (dd, J=8.5, 2.1 Hz, 1H), 6.45 (q, J=7.1 Hz, 1H), 4.24 (t,J=8.5 Hz, 2H), 3.97-3.92 (m, 2H), 3.73 (t, J=4.6 Hz, 2H), 3.08-2.97 (m,2H), 2.72-2.62 (m, 3H), 2.29-2.19 (m, 1H), 2.12-1.96 (m, 2H), 1.93 (d,J=7.1 Hz, 3H), 1.89-1.73 (m, 3H), 1.06-0.97 (m, 1H). LCMS [M+H]: 543.0.

Example 45

N-(2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)acetamideandN-(2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)acetamide.Prepared as a mixture of the above two diastereomers according togeneral procedure A using 2-(1,3-dioxoisoindolin-2-yl)acetaldehyde,deprotection with 5 equiv of hydrazine hydrate in methanol over 5 h, andacylation with 1.2 equiv of acetic anhydride in dichloromethane with 2equiv of trimethylamine, followed by procedure C and condensation of theresulting diasteromeric mixture product with Precursor V using procedureD (a). [M+H] 584.0.

Example 46

N-(2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)methanesulfonamideandN-(2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)methanesulfonamide.Prepared as a mixture of the above two diastereomers using generalprocedure A using 2-(1,3-dioxoisoindolin-2-yl)acetaldehyde, deprotectionwith 5 equiv of hydrazine hydrate in methanol over 5 h, and reactionwith 1.2 equiv mesyl chloride in dichloromethane with 2 equiv oftrimethylamine, followed by procedure C and the resulting diasteromericmixture product was condensed with Precursor V using procedure D (a).[M+H] 620.1.

Example 47

N-(2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)propane-2-sulfonamideand N-(2-((S)-3-(1-(1-((R) -1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)propane-2-sulfonamidePrepared as a mixture of the above two diastereomers employing generalprocedure A using 2-(1,3-dioxoisoindolin-2-yl)acetaldehyde, deprotectionwith 5 equiv of hydrazine hydrate in methanol over 5 h, and reactionwith 1.2 equiv isopropylsulfonyl chloride in dichloromethane with 2equiv of trimethylamine, followed by procedure C. The resultingdiasteromeric mixture product was condensed with Precursor V usingprocedure D (a). [M+H] 648.1.

Example 48

N-(2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)isobutyramideandN-(2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)isobutyramide.Prepared as a mixture of the above two diastereomers using generalprocedure A using 2-(1,3-dioxoisoindolin-2-yl)acetaldehyde, deprotectionwith 5 equiv of hydrazine hydrate in methanol over 5 h, and reactionwith 1.2 equiv 2-methylpropionyl chloride in dichloromethane with 2equiv of trimethylamine, followed by procedure C. The resultingdiasteromeric mixture product was condensed with Precursor V usingprocedure D (a).[M+H] 612.2.

Example 49

Methyl(2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)carbamateand methyl(2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)carbamate.Prepared as a mixture of the above two diastereomers using generalprocedure A using 2-(1,3-dioxoisoindolin-2-yl)acetaldehyde, deprotectionwith 5 equiv of hydrazine hydrate in methanol over 5 h, and reactionwith 1.2 equiv methyl chlorofomate in dichloromethane with 2 equiv oftrimethylamine, followed by procedure C. The resulting diasteromericmixture product was condensed with Precursor V using procedure D (a).[M+H] 600.1.

Example 50

1-((R)-1-(2,4-Dichlorophenyl)ethyl)-6-(3-((R)-1-(3-(methylsulfonyl)propyl)piperidin-3-yl)azetidin-1-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazineand1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((S)-1-(3-(methylsulfonyl)propyl)piperidin-3-yl)azetidin-1-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine.Prepared as a mixture of the above two diastereomers employing generalprocedure B (b) using 1-bromo-3-(methylsulfonyl)propane, followed byprocedure C and the resulting diasteromeric mixture product wascondensed with Precursor V using procedure D (a). [M+H] 619.0.

Example 51

N-(2-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)isobutyramide.The diastereomers prepared in Example 48 were separated on AD-H 20×250mm column using 25% ethanol (0.1% diethylamine) and 100 bar CO₂. Thefirst eluting diastereomer had the structure indicated above.¹H NMR (400MHz, CD₃OD, HCl salt): δ ppm 7.93 (s, 1H), 7.47 (d, J=2.0 Hz, 1H), 7.33(d, J=8.5 Hz, 1H), 7.29 (dd, J=8.5, 2.0 Hz, 1H), 6.43 (q, J=7.1 Hz, 1H),4.31 (t, J=8.7 Hz, 2H), 4.09-3.98 (m, 2H), 3.57 (d, J=5.8 Hz, 3H), 3.21(d, J=2.8 Hz, 2H), 2.92 (s, 1H), 2.69 (s, 2H), 2.48 (dt, J=13.8, 6.9 Hz,1H), 2.21-2.07 (m, 1H), 2.07-1.92 (m, 2H), 1.90 (d, J=7.1 Hz, 3H),1.87-1.75 (m, 1H), 1.34-1.18 (m, 2H), 1.16-1.09 (m, 6H). [M+H] 612.2.

Example 52

N-(2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)isobutyramide.The diastereomers prepared in Example 48 were separated on AD-H 20×250mm column using 25% ethanol (0.1% diethylamine) and 100 bar CO₂. Thesecond eluting diastereomer had the structure indicated above. ¹H NMR(400 MHz, CD₃OD, HCl salt) δ ppm 7.93 (d, J=0.6 Hz, 1H), 7.48 (d, J=2.1Hz, 1H), 7.35 (d, J=8.5 Hz, 1H), 7.30 (dd, J=8.5, 2.1 Hz, 1H), 6.44 (q,J=6.9 Hz, 1H), 4.39-4.22 (m, 2H), 4.07-3.97 (m, 2H), 3.60-3.38 (m, 3H),3.09 (br s, 2H), 2.87-2.41 (m, 4H), 2.47 (dt, J=13.7, 6.8 Hz, 1H),2.16-2.02 (m, 1H), 2.02-1.93 (m, 2H), 1.90 (d, J=7.1 Hz, 3H), 1.85-1.71(m, 1H), 1.37-1.15 (m, 1H), 1.13 (d, J=6.9 Hz, 6H). [M+H] 612.2.

Example 53

N-(2-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)acetamide.The diastereomers prepared in Example 45 were separated on AD-H 20×250mm column using 20% methanol (0.1% diethylamine) and 100 bar CO₂. Thefirst eluting diastereomer had the structure indicated above. ¹H NMR(400 MHz, CD₃OD, HCl salt): δ ppm 7.93 (s, 1H), 7.47 (d, J=2.0 Hz, 1H),7.34 (d, J=8.5 Hz, 1H), 7.29 (dd, J=8.5, 1.9 Hz, 1H), 6.43 (q, J=7.0 Hz,1H), 4.31 (t, J=8.7 Hz, 2H), 4.10-3.99 (m, 2H), 3.77-3.49 (m, 4H), 3.25(t, J=5.8 Hz, 2H), 2.92 (t, J=11.3 Hz, 1H), 2.67 (t, J=12.0 Hz, 2H),2.14 (d, J=9.8 Hz, 1H), 2.08-1.92 (m, 2H), 1.99 (s, 3H), 1.90 (d, J=7.1Hz, 3H), 1.88-1.77 (m, 1H), 1.27-1.16 (m, 1H). [M+H] 584.0.

Example 54

N-(2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)acetamideThe diastereomers prepared in Example 45 were separated on AD-H 20×250mm column using 20% methanol (0.1% diethylamine) and 100 bar CO₂. Thesecond eluting diastereomer had the structure indicated above. ¹H NMR(400 MHz, CD₃OD, HCl salt): δ ppm 7.93 (s, 1H), 7.48 (s, 1H), 7.35 (d,J=8.5 Hz, 1H), 7.30 (dd, J=8.5, 2.0 Hz, 1H), 6.44 (q, J=7.1 Hz, 1H),4.36-4.25 (m, 2H), 4.08-3.96 (m, 2H), 3.65-3.42 (m, 4H), 3.15-3.06 (m,2H), 2.84-2.62 (m, 2H), 2.60-2.44 (m, 1H), 2.05 (s, 1H), 1.98 (s, 3H),2.02-1.93 (m, 2H), 1.90 (d, J=7.1 Hz, 3H), 1.86-1.71 (m, 1H), 1.25-1.10(m, 1H). [M+H] 584.0.

Example 55

1-((R)-1-(4-chloro-2-fluorophenyl)ethyl)-6-(3-((R)-1-(2-hydroxyethyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.The title compound was prepared using general procedure B with PrecursorVI and 2-bromoethan-1-ol, followed by procedure C. The resulting productwas condensed with Precursor VIII using procedure D and converted to thecorresponding HCl salt by dissolution in EtOH, cooling to 0° C., andaddition of 1 equiv. of 0.01M HCl in EtOH. ¹H NMR (300 MHz, Methanol-d₄;HCl Salt) δ 7.92 (s, 1H), 7.37 (t, J=8.1 Hz, 1H), 7.22-7.17 (m, 2H),6.34 (q, J=6.9 Hz, 1H), 4.32 (q, J=9.0 Hz, 2H), 4.03 (t, J=7.2 Hz, 2H),3.87 (t, J=5.1 Hz, 2H), 3.55-3.41 (m, 2H), 3.17-3.08 (m, 2H), 2.78-2.52(m, 2H), 2.18-2.06 (m, 1H), 1.98-1.75 (m, 4H), 1.92 (d, J=7.2 Hz, 3H),1.24-1.12 (m, 1H). LCMS [M+H] 484.1.

Example 56

1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((S)-1-(4-hydroxy-4-methylpentyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrileand1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-(4-hydroxy-4-methylpentyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.tert-Butyl3-(1-(4-methoxy-4-oxobutyl)piperidin-3-yl)azetidine-1-carboxylate wasprepared using general procedure A with methyl 4-oxobutanoate. Thetert-butyl3-(1-(4-methoxy-4-oxobutyl)piperidin-3-yl)azetidine-1-carboxylate (251mg, 0.737 mmol) was dissolved in tetrahydrofurane (“THF”) (7 mL) andtreated with a 3M solution of methyl magnesium bromide in diethyl ether(0.61 mL, 1.84 mmol, 2.5 eq) at −78° C. The solution was stirred for 1h, then warmed to room temperature and quenched with saturated aq.ammonium chloride (25 mL) and extracted with ethyl acetate (3×25 mL).The organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. tert-butyl3-(1-(4-hydroxy-4-methylpentyl)piperidin-3-yl)azetidine-1-carboxylatewas isolated by flash column chromatography (silica gel, 0-10% 7N NH₃ inmethanol in DCM) (176 mg, 70% yield). The title compound as a mixture ofthe two diastereomers was prepared from tert-butyl3-(1-(4-hydroxy-4-methylpentyl)piperidin-3-yl)azetidine-1-carboxylateusing general procedures C and D using Precursor IV. ¹H NMR (400 MHz,Methanol-d₄, trifluoroacetic acid salt): δ 7.96 (s, 1H), 7.51-7.45 (m,1H), 7.38-7.33 (m, 1H), 7.31 (dd, J=8.5, 2.1 Hz, 1H), 6.45 (q, J=7.0 Hz,1H), 4.40-4.23 (m, 2H), 4.12-3.94 (m, 2H), 3.57 (dd, J=23.3, 12.2 Hz,2H), 3.16-3.07 (m, 2H), 2.95-2.80 (m, 1H), 2.77-2.57 (m, 2H), 2.15-1.70(m, 9H), 1.59-1.47 (m, 2H), 1.34-1.08 (m, 7H). LCMS

[M+H] 557.1.

Example 57

2-(S)-3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)-N-methylethane-1-sulfonamideand2-((R)-3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)-N-methylethane-1-sulfonamide.tert-Butyl3-[1-(2-fluorosulfonylethyl)-3-piperidyl]azetidine-1-carboxylate wasprepared from vinyl sulfonyl fluoride according to general procedure B.To tert-butyl3-[1-(2-fluorosulfonylethyl)-3-piperidyl]azetidine-1-carboxylate (231mg, 0.66 mmol) in THF (3 mL) was added a 33% solution of methylamine inethanol (0.6 mL, 6.6 mmol, 10 equiv.). The mixture was heated in asealed tube at 70° C. for 2.5 h. The mixture was concentrated in vacuo,and the residue was purified by flash column chromatography (silica gel,0-10% 7N NH₃ in methanol in DCM) (133 mg, 56% yield). The title compoundas a mixture of the two diastereomers was prepared from tert-butyl3-[1-[2-(methylsulfamoyl)ethyl]-3-piperidyl]azetidine-1-carboxylateaccording to general procedures C and D using Precursor IV. ¹H NMR (400MHz, Methanol-d₄, free base): δ 7.95 (s, 1H), 7.48 (d, J=2.1 Hz, 1H),7.38 (dd, J=8.6, 1.2 Hz, 1H), 7.31 (dd, J=8.5, 2.2 Hz, 1H), 6.45 (q,J=7.1 Hz, 1H), 4.33-4.19 (m, 2H), 4.04-3.88 (m, 2H), 3.29-3.21 (m, 2H),2.94-2.86 (m, 2H), 2.86-2.75 (m, 2H), 2.71 (s, 3H), 2.68-2.55 (m, 1H),2.08 (s, 1H), 1.90 (d, J=7.1 Hz, 3H), 1.87-1.69 (m, 4H), 1.66-1.52 (m,1H), 1.03-0.87 (m, 1H). LCMS [M+H] 577.0.

Example 58

1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((S)-1-(2-(morpholinosulfonyl)ethyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrileand1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-(2-(morpholinosulfonyl)ethyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.tert-Butyl3-[1-(2-fluorosulfonylethyl)-3-piperidyl]azetidine-1-carboxylate wasprepared from vinyl sulfonyl fluoride according to general procedure B.To tert-butyl3-[1-(2-fluorosulfonylethyl)-3-piperidyl]azetidine-1-carboxylate (230mg, 0.53 mmol) and N,N-diisopropyl-N-ethylamine (85 mg, 0.66 mmol, 1.0equiv.) in THF (3 mL) is added morpholine (69 mg, 0.79 mmol, 1.2equiv.). The mixture was heated in a sealed tube at 70° C. for 2.5 h andconcentrated in vacuo. The residue was purified by flash columnchromatography (silica gel, 0-10% 7N NH₃ in methanol in DCM) to affordtert-butyl3-[1-(2-morpholinosulfonylethyl)-3-piperidyl]azetidine-1-carboxylate(230 mg, 83% yield). The title compound as a mixture of the twodiastereomers was prepared from tert-butyl3-[1-(2-morpholinosulfonylethyl)-3-piperidyl]azetidine-1-carboxylateaccording to general procedures C and D using Precursor IV. ¹H NMR (400MHz, Methanol-d₄, trifluoroacetic acid salt): δ 7.97 (s, 1H), 7.48 (dd,J=2.1, 0.4 Hz, 1H), 7.35 (dd, J=8.5, 2.8 Hz, 1H), 7.31 (dd, J=8.5, 2.1Hz, 1H), 6.45 (q, J=7.1 Hz, 1H), 4.88-4.87 (m, 4H), 4.40-4.25 (m, 2H),4.13-3.95 (m, 2H), 3.79-3.50 (m, 8H), 3.33-3.29 (m, 2H), 3.05-2.88 (m,1H), 2.85-2.62 (m, 2H), 2.17-1.94 (m, 3H), 1.90 (d, J=7.1 Hz, 3H),1.88-1.71 (m, 1H), 1.34-1.12 (m, 1H). LCMS [M+H] 633.1.

Example 59

6-(3-((S)-14(1H-pyrazol-3-yl)methyl)piperidin-3-yl)azetidin-1-yl)-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrileand6-(3-((R)-1-((1H-pyrazol-3-yl)methyl)piperidin-3-yl)azetidin-1-yl)-1-((R)-1-(2,4-dichl orophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile. Thetitle compound as a mixture of the two diastereomers was prepared usinggeneral procedure A using 1H-pyrazole-3-carbaldehyde and 4:2:11,2-dichloroethane/dimethylformamide (“DMF”)/trifluoroethanol as thesolvent, followed by procedure C. The resulting product was condensedwith Precursor IV using procedure D. ¹H NMR (400 MHz, Methanol-d₄, freebase): δ 7.93 (s, 1H), 7.63 (s, 1H), 7.48 (dd, J=2.1, 1.3 Hz, 1H), 7.38(dd, J=8.5, 1.1 Hz, 1H), 7.31 (dd, J=8.5, 2.1 Hz, 1H), 6.45 (q, J=7.1Hz, 1H), 6.32 (s, 1H), 4.32-4.14 (m, 2H), 4.04-3.81 (m, 2H), 3.70-3.53(m, 2H), 3.02-2.72 (m, 2H), 2.71-2.47 (m, 1H), 2.12-1.98 (m, 1H), 1.90(d, J=7.1 Hz, 3H), 1.86-1.68 (m, 4H), 1.68-1.43 (m, 1H), 1.07-0.76 (m,1H). LCMS [M+H] 536.0.

Example 60

6-(3-((S)-1-(1H-imidazol-4-yl)methyl)piperidin-3-yl)azetidin-1-yl)-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrileand6-(3-((R)-1-((1H-imidazol-4-yl)methyl)piperidin-3-yl)azetidin-1-yl)-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.The title compound as a mixture of the two diastereomers was preparedusing general procedure A from 1H-imidazole-5-carbaldehyde using 2:11,2-dichloroethane/DMF as the solvent, followed by procedure C. Theresulting product was condensed with Precursor IV using procedure D. ¹HNMR (400 MHz, Methanol-d₄, free base): δ 7.94 (s, 1H), 7.71 (dd, J=2.0,1.2 Hz, 1H), 7.48 (dd, J=2.1, 1.6 Hz, 1H), 7.37 (dd, J=8.5, 1.4 Hz, 1H),7.31 (dd, J=8.5, 2.1 Hz, 1H), 7.13 (s, 1H), 6.45 (q, J=7.0 Hz, 1H),4.34-4.16 (m, 2H), 4.06-3.84 (m, 2H), 3.80 (s, 2H), 3.16-3.01 (m, 2H),2.69-2.55 (m, 1H), 2.42-2.25 (m, 1H), 2.12-1.97 (m, 1H), 1.99-1.76 (m,6H), 1.73-1.57 (m, 1H), 1.06-0.92 (m, 1H). LCMS [M+H] 536.0.

Example 61

1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrileand1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((S)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.The title compound as a mixture of the two diastereomers was preparedfrom tetrahydro-4H-thiopyran-4-one 1,1-dioxide by general procedure Ausing 2:1 1,2-dichloroethane/DMF as the solvent, followed by procedureC. The resulting product was treated with Precursor IV using generalprocedure D. ¹H NMR (400 MHz, Methanol-d₄, free base): δ 7.94 (s, 1H),7.48 (d, J=2.1 Hz, 1H), 7.38 (dd, J=8.6, 1.2 Hz, 1H), 7.31 (dd, J=8.5,2.1 Hz, 1H), 6.45 (q, J=7.1 Hz, 1H), 4.36-4.18 (m, 2H), 4.03-3.86 (m,2H), 3.19-3.02 (m, 4H), 2.87-2.79 (m, 2H), 2.75-2.58 (m, 2H), 2.27 (t,J=10.9 Hz, 1H), 2.22-2.04 (m, 5H), 2.03-1.94 (m, 1H), 1.90 (d, J=7.0 Hz,3H), 1.87-1.70 (m, 2H), 1.66-1.45 (m, 1H), 1.03-0.87 (m, 1H). LCMS [M+H]588.0.

Example 62

1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-(tetrahydro-2H-pyran-4-yl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrileand1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((S)-1-(tetrahydro-2H-pyran-4-yl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.The title compound as a mixture of the two diastereomers was preparedfrom tetrahydro-4H-pyran-4-one by general procedure A, followed byprocedure C. The resulting product was treated with Precursor IV usinggeneral procedure D. ¹H NMR (400 MHz, Methanol-d₄, free base): δ 7.95(s, 1H), 7.48 (dd, J=2.2, 1.0 Hz, 1H), 7.41-7.34 (m, 1H), 7.31 (dd,J=8.5, 2.1 Hz, 1H), 6.45 (q, J=7.1 Hz, 1H), 4.34-4.20 (m, 2H), 4.04-3.90(m, 4H), 3.40 (t, J=11.8 Hz, 2H), 3.05-2.90 (m, 2H), 2.68-2.46 (m, 2H),2.25-2.12 (m, 1H), 1.90 (d, J=7.1 Hz, 3H), 1.88-1.71 (m, 5H), 1.68-1.48(m, 4H), 1.02-0.86 (m, 1H). LCMS [M+H] 540.0.

Example 63

N-(2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)acetamideandN-(2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)acetamide.The title compound as a mixture of the two diastereomers was preparedusing general procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal,followed by removal of phthaloyl group with hydrazine hydrate (4 equiv.)in methanol (0.4M) at ambient temperature for 18 hours. The reactionmixture was diluted with water, extracted with DCM, and the organiclayer was dried over sodium sulfate, filtered and concentrated invacuum. Crude tert-Butyl3-[1-(2-aminoethyl)-3-piperidyl]azetidine-1-carboxylate (120 mg, 0.423mmol) in DCM (2 mL) was treated with triethylamine (129 mg, 1.27 mmol,3.0 equiv.) and acetyl chloride (40.0 mg, 0.51 mmol, 1.2 equiv). After30 min, the mixture was quenched with 1M aq. sodium carbonate (10 mL)and extracted with ethyl acetate (3×10 mL). The combined organic layerswere dried over sodium sulfate, filtered, and concentrated in vacuo toafford tert-butyl3-(1-(2-acetamidoethyl)piperidin-3-yl)azetidine-1-carboxylate. The titlecompound as a mixture of the two diastereomers was prepared fromtert-butyl 3-(1-(2-acetamidoethyl)piperidin-3-yl)azetidine-1-carboxylateaccording to general procedures C and D using Precursor II. ¹H NMR (400MHz, Methanol-d₄, trifluoroacetic acid salt): δ 7.75 (s, 1H), 7.44 (dd,J=2.2, 1.3 Hz, 1H), 7.35 (dd, J=8.5, 2.4 Hz, 2H), 7.27-7.21 (m, 1H),6.31-6.25 (m, 1H), 4.34-4.19 (m, 2H), 4.04-3.93 (m, 2H), 3.81-3.42 (m,4H), 3.23 (t, J=5.9 Hz, 2H), 2.98-2.83 (m, 1H), 2.71-2.59 (m, 2H), 2.50(s, 3H), 2.12-1.93 (m, 5H), 1.88-1.74 (m, 4H), 1.30-1.16 (m, 1H). LCMS[M+H] 530.0.

Example 64

N-[2-[(R)-3-[1-[1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-3-methyl-pyrazolo[3,4-b]pyrazin-6-yl]azetidin-3-yl]-1-piperidyl]ethyl]methanesulfonamideandN-[2-[(S)-3-[1-[1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-3-methyl-pyrazolo[3,4-b]pyrazin-6-yl]azetidin-3-yl]-1-piperidyl]ethyl]methanesulfonamide.The title compound as a mixture of the two diastereomers was preparedusing general procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal,followed by removal of phthaloyl group with hydrazine hydrate (4 equiv.)in methanol (0.4M) at ambient temperature for 18 hours. The reactionmixture was diluted with water, extracted with DCM, organic layer wasdried over sodium sulfate, filtered and concentrated in vacuum. Crudetert-butyl 3-[1-(2-aminoethyl)-3-piperidyl]azetidine-1-carboxylate (120mg, 0.423 mmol) in DCM (2 mL) was treated with triethylamine (129 mg,1.27 mmol, 3.0 equiv.) and methanesulfonyl chloride (58 mg, 0.51 mmol,1.2 equiv). After 30 min, the mixture was quenched with 1M aq. sodiumcarbonate (10 mL) and extracted with ethyl acetate (3×10 mL). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo to afford tert-butyl3-(1-(2-(methylsulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylate.The title compound as a mixture of the two diastereomers was preparedfrom tert-butyl3-(1-(2-(methylsulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylateaccording to general procedures C and D using Precursor II. ¹H NMR (400MHz, Methanol-d₄, trifluoroacetic acid salt): δ 7.73 (s, 1H), 7.44 (d,J=2.1 Hz, 1H), 7.37 (dd, J=8.5, 2.2 Hz, 1H), 7.30-7.21 (m, 1H),6.33-6.23 (m, 1H), 4.33-4.20 (m, 2H), 4.03-3.91 (m, 2H), 3.77-3.59 (m,2H), 3.59-3.40 (m, 2H), 3.30-3.25 (m, 2H), 3.02 (s, 3H), 3.00-2.87 (m,1H), 2.75-2.57 (m, 2H), 2.50 (s, 3H), 2.21-1.93 (m, 3H), 1.93-1.74 (m,4H), 1.30-1.09 (m, 1H). [M+H] 566.0.

Example 65

N-(2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)propane-2-sulfonamideandN-(2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)propane-2-sulfonamide.The title compound as a mixture of the two diastereomers was preparedusing general procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal,followed by removal of phthaloyl group with hydrazine hydrate (4 equiv.)in methanol (0.4M) at ambient temperature for 18 hours. The reactionmixture was diluted with water, extracted with DCM, organic layer wasdried over sodium sulfate, filtered and concentrated in vacuum. Crudetert-butyl 3-[1-(2-aminoethyl)-3-piperidyl]azetidine-1-carboxylate (120mg, 0.423 mmol) in DCM (2 mL) was treated with triethylamine (129 mg,1.27 mmol, 3.0 equiv.) and 2-propanesulfonyl chloride (73 mg, 0.51 mmol,1.2 equiv). After 30 min, the mixture was quenched with 1M aq. sodiumcarbonate (10 mL) and extracted with ethyl acetate (3×10 mL). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo to afford tert-butyl3-(1-(2-((1-methylethyl)sulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylate.The title compound as a mixture of the two diastereomers was preparedfrom tert-butyl3-(1-(2-((1-methylethyl)sulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylateaccording to general procedures C and D using Precursor II. ¹H NMR (400MHz, Methanol-d₄, trifluoroacetic acid salt): δ 7.74 (s, 1H), 7.46-7.42(m, 1H), 7.37 (d, J=8.5 Hz, 1H), 7.26 (dd, J=8.5, 2.1 Hz, 1H), 6.34-6.21(m, 1H), 4.33-4.18 (m, 2H), 4.05-3.94 (m, 2H), 3.78-3.59 (m, 2H),3.59-3.41 (m, 2H), 3.36-3.19 (m, 4H), 3.03-2.92 (m, 1H), 2.75-2.57 (m,2H), 2.50 (s, 3H), 2.21-1.93 (m, 2H), 1.93-1.76 (m, 4H), 1.41-1.32 (m,6H), 1.28-1.12 (m, 1H). LCMS [M+H] 594.0.

Example 66

N-(2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)propane-2-sulfonamideandN-(2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)propane-2-sulfonamide.The title compound as a mixture of the two diastereomers was preparedfrom tert-butyl3-(1-(2-((l-methylethyl)sulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylate(see preparation in the previous example) according to generalprocedures C and D using Precursor V. ¹H NMR (400 MHz, Methanol-d₄,trifluoroacetic acid salt): δ 7.75 (s, 1H), 7.45-7.40 (m, 1H), 7.35 (dd,J=8.5, 4.3 Hz, 1H), 7.26 (dd, J=8.5, 2.2 Hz, 1H), 6.33-6.24 (m, 1H),4.34-4.20 (m, 2H), 4.06-3.92 (m, 2H), 3.73-3.49 (m, 4H), 3.24 (t, J=6.2Hz, 2H), 2.93 (t, J=12.7 Hz, 1H), 2.75-2.58 (m, 2H), 2.54-2.40 (m, 4H),2.17-1.90 (m, 3H), 1.90-1.84 (m, 3H), 1.84-1.72 (m, 1H), 1.30-1.17 (m,1H), 1.17-1.09 (m, 6H). LCMS [M+H] 558.1.

Example 67

Methyl(2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)carbamateand methyl(2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)carbamate.The title compound as a mixture of the two diastereomers was preparedusing general procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal,followed by removal of phthaloyl group with hydrazine hydrate (4 equiv.)in methanol (0.4M) at ambient temperature for 18 hours. The reactionmixture was diluted with water, extracted with DCM, organic layer wasdried over sodium sulfate, filtered and concentrated in vacuum. Crudetert-butyl 3-[1-(2-aminoethyl)-3-piperidyl]azetidine-1-carboxylate (120mg, 0.423 mmol) in DCM (2 mL) was treated with triethylamine (129 mg,1.27 mmol, 3.0 equiv.) and methyl chloroformate (48 mg, 0.51 mmol, 1.2equiv). After 30 min, the mixture was quenched with 1M aq. sodiumcarbonate (10 mL) and extracted with ethyl acetate (3×10 mL). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo to afford tert-butyl3-(1-(2-((methoxycarbonyl)amino)ethyl)piperidin-3-yl)azetidine-1-carboxylate.The title compound as a mixture of the two diastereomers was preparedfrom tert-butyl3-(1-(2-((methoxycarbonyl)amino)ethyl)piperidin-3-yl)azetidine-1-carboxylateusing general procedures C and D using Precursor II. ¹H NMR (400 MHz,Methanol-d₄, trifluoroacetic acid salt): δ 7.74 (s, 1H), 7.48-7.40 (m,1H), 7.35 (dd, J=8.5, 2.2 Hz, 1H), 7.26 (dd, J=8.5, 2.2 Hz, 1H),6.34-6.23 (m, 1H), 4.35-4.22 (m, 2H), 4.05-3.91 (m, 2H), 3.76-3.61 (m,5H), 3.60-3.42 (m, 2H), 3.24 (t, J=5.9 Hz, 2H), 2.98-2.84 (m, 1H),2.71-2.59 (m, 2H), 2.50 (s, 3H), 2.16-1.93 (m, 3H), 1.93-1.72 (m, 4H),1.30-1.12 (m, 1H). LCMS [M+H] 546.0.

Example 68

4-(S)-3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)-N-methylbutanamide.tert-Butyl3-[1-(4-methoxy-4-oxo-butyl)-3-piperidyl]azetidine-1-carboxylate wasprepared from methyl 4-oxobutanoate according to general procedure A.tert-Butyl3-(1-(4-methoxy-4-oxobutyl)piperidin-3-yl)azetidine-1-carboxylate washydrolyzed with 4 equiv. of lithium hydroxide in methanol/water (3:1 byvolume) mixture at ambient temperature for 18 hours, followed byremoving methanol in vacuum, acidifying reaction mixture with conc. HCluntil pH 7 and extracting with DCM. Drying with sodium sulfate,filtering, and removing solvent in vacuum afforded the correspondingacid as a white solid.4-(3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)butanoic acid(288 mg, 0.88 mmol) in DMF (5 mL) was treated with HATU (402 mg, 1.06mmol, 1.2 equiv.). The mixture was stirred for 5 min, thenN,N-diisopropyl-N-ethylamine (0.46 mL, 2.65 mmol, 3.0 equiv.) was added.After 10 min, a 33% solution of methylamine in ethanol (0.15 mL, 4.4mmol, 5.0 equiv.) was added and the reaction was allowed to stirovernight. The reaction was quenched with 1M aq. sodium carbonate (5mL), diluted with ethyl acetate (10 mL), and the organic layer waswashed with water (3×5 mL). The organic layer was dried over sodiumsulfate, filtered, and concentrated in vacuo to afford tert-butyl3-[1-[4-(methylamino)-4-oxo-butyl]-3-piperidyl]azetidine-1-carboxylate.4-(3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)-N-methylbutanamidewas prepared from tert-butyl3-[1-[4-(methylamino)-4-oxo-butyl]-3-piperidyl]azetidine-1-carboxylateusing general procedures C and D using Precursor IV. The title compoundwas isolated by chiral supercritical fluid chromatography (“SFC”) (OD-H,30% methanol (0.1% diethylamine)/CO₂ 100 bars) as the first elutingpeak. ¹H NMR (400 MHz, Methanol-d₄, free base): δ 7.92 (s, 1H), 7.46 (d,J=2.1 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 7.30 (dd, J=8.5, 2.1 Hz, 1H),6.44 (q, J=7.0 Hz, 1H), 4.25 (t, J=8.1 Hz, 2H), 4.02-3.86 (m, 2H),2.99-2.83 (m, 2H), 2.83-2.51 (m, 2H), 2.71 (s, 3H), 2.40-2.30 (m, 2H),2.19 (t, J=7.4 Hz, 2H), 2.04-1.92 (m, 1H), 1.90 (d, J=7.1 Hz, 3H),1.87-1.50 (m, 5H), 1.23-1.12 (m, 1H), 1.01-0.81 (m, 1H). LCMS [M+H]555.1.

Example 69

4-((R)-3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)-N-methylbutanamide.tert-Butyl3-[1-(4-methoxy-4-oxo-butyl)-3-piperidyl]azetidine-1-carboxylate wasprepared from methyl 4-oxobutanoate according to general procedure A.tert-Butyl3-(1-(4-methoxy-4-oxobutyl)piperidin-3-yl)azetidine-1-carboxylate washydrolyzed with 4 equiv. of lithium hydroxide in methanol/water (3:1 byvolume) mixture at ambient temperature for 18 hours, followed byremoving methanol in vacuum, acidifying reaction mixture with conc. HCluntil pH 7 and extracting with DCM. Drying with sodium sulfate,filtering, and removing solvent in vacuum afforded the correspondingacid as a white solid.4-(3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)butanoic acid(288 mg, 0.88 mmol) in DMF (5 mL) was treated with HATU (402 mg, 1.06mmol, 1.2 equiv.). The mixture was stirred for 5 min, thenN,N-diisopropyl-N-ethylamine (0.46 mL, 2.65 mmol, 3.0 equiv.) was added.After 10 min, a 33% solution of methylamine in ethanol (0.15 mL, 4.4mmol, 5.0 equiv.) was added and the reaction was allowed to stirovernight. The reaction was quenched with 1M aq. sodium carbonate (5mL), diluted with ethyl acetate (10 mL), and the organic layer waswashed with water (3×5 mL). The organic layer was dried over sodiumsulfate, filtered, and concentrated in vacuo to afford tert-butyl3-[1-[4-(methylamino)-4-oxo-butyl]-3-piperidyl]azetidine-1-carboxylate.4-(3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)-N-methylbutanamidewas prepared from tert-butyl3-[1-[4-(methylamino)-4-oxo-butyl]-3-piperidyl]azetidine-1-carboxylateusing general procedures C and D using Precursor IV. The title compoundwas isolated by chiral SFC chromatography (OD-H, 30% methanol (0.1%diethylamine)/CO₂ 100 bars) as the second eluting peak. ¹H NMR (400 MHz,Methanol-d₄, free base): δ 7.92 (s, 1H), 7.46 (d, J=2.1 Hz, 1H), 7.37(d, J=8.5 Hz, 1H), 7.30 (dd, J=8.5, 2.1 Hz, 1H), 6.44 (q, J=7.0 Hz, 1H),4.31-4.18 (m, 2H), 4.02-3.86 (m, 2H), 2.96-2.83 (m, 2H), 2.70 (s, 3H),2.75-2.52 (m, 2H), 2.41-2.30 (m, 2H), 2.19 (t, J=7.4 Hz, 2H), 2.01-1.92(m, 1H), 1.90 (d, J=7.0 Hz, 3H), 1.86-1.50 (m, 5H), 1.15 (t, J=7.2 Hz,1H), 1.00-0.84 (m, 1H). LCMS [M+H] 555.1.

Example 70

1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((S)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.tert-butyl3-[1-(2-ethoxy-2-oxo-ethyl)-3-piperidyl]azetidine-1-carboxylate wasprepared from ethyl glyoxylate according to general procedure A.tert-Butyl3-[1-(2-ethoxy-2-oxo-ethyl)-3-piperidyl]azetidine-1-carboxylate (240 mg,0.74 mmol) in anhydrous THF (7 mL) was cooled to −78° C. and MeMgBr wasadded as a 3M solution in diethyl ether (0.52 mL, 1.54 mmol, 2.1equiv.). The mixture was warmed to 0° C. and let stir for 1 h beforebeing quenched with sat. aq. ammonium chloride (5 mL) and extracted withDCM (10 mL). The organic layer was dried over magnesium sulfate,filtered, and concentrated in vacuo. The residue was purified by flashcolumn chromatography (silica gel, 0-10% methanol in DCM) to affordtert-butyl3-(1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)azetidine-1-carboxylate(100 mg, 43% yield).1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-(1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrilewas prepared from tert-butyl3-(1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)azetidine-1-carboxylateusing general procedures C and D using Precursor IV. The title compoundwas isolated by chiral SFC (AD-H, 40% isopropanol (0.1%diethylamine)/CO₂ 100 bars) as the first eluting peak. ¹H NMR (400 MHz,Methanol-d₄, free base): δ 7.94 (s, 1H), 7.48 (d, J=2.1 Hz, 1H), 7.38(d, J=8.5 Hz, 1H), 7.31 (dd, J=8.5, 2.2 Hz, 1H), 6.50-6.40 (m, 1H),4.30-4.20 (m, 2H), 3.98-3.85 (m, 2H), 3.40-3.21 (m, 2H), 2.95-2.75 (m,2H), 2.75-2.62 (m, 1H), 2.34-2.11 (m, 2H), 2.06-1.80 (m, 4H), 1.80-1.47(m, 3H), 1.18 (d, J=3.9 Hz, 3H), 1.15 (d, J=6.1 Hz, 3H), 1.06-0.81 (m,1H). LCMS [M+H] 528.1.

Example 71

1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.tert-butyl3-[1-(2-ethoxy-2-oxo-ethyl)-3-piperidyl]azetidine-1-carboxylate wasprepared from ethyl glyoxylate according to general procedure A.tert-butyl3-[1-(2-ethoxy-2-oxo-ethyl)-3-piperidyl]azetidine-1-carboxylate (240 mg,0.74 mmol) in THF (7 mL) was cooled to −78° C. and MeMgBr was added as a3M solution in diethyl ether (0.52 mL, 1.54 mmol, 2.1 equiv.). Themixture was warmed to 0° C. and let stir for 1 h before being quenchedwith sat. aq. ammonium chloride (5 mL) and extracted with DCM (10 mL).The organic layer was dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was purified by flash columnchromatography (silica gel, 0-10% methanol in DCM) to afford tert-butyl3-(1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)azetidine-1-carboxylate(100 mg, 43% yield).1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-(1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrilewas prepared from tert-butyl3-(1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)azetidine-1-carboxylateusing general procedures C and D using Precursor IV. The title compoundwas isolated from its diastereomer by chiral SFC (AD-H, 40% isopropanol(0.1% diethylamine)/CO₂ 100 bars) as the second eluting peak. ¹H NMR(400 MHz, Methanol-d₄, free base): δ 7.94 (s, 1H), 7.48 (d, J=2.1 Hz,1H), 7.38 (d, J=8.5 Hz, 1H), 7.31 (dd, J=8.5, 2.1 Hz, 1H), 6.44 (q,J=7.1 Hz, 1H), 4.33-4.19 (m, 2H), 4.00-3.85 (m, 2H), 3.33-3.28 (m, 2H),2.98-2.78 (m, 2H), 2.73-2.61 (m, 1H), 2.36-2.11 (m, 2H), 2.04-1.81 (m,4H), 1.79-1.55 (m, 3H), 1.18 (d, J=3.9 Hz, 3H), 1.15 (d, J=6.2 Hz, 3H),1.04-0.84 (m, 1H). LCMS [M+H] 528.1.

Example 72

1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((S)-1-propylpiperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.tert-Butyl 3-(1-propylpiperidin-3-yl)azetidine-1-carboxylate wasprepared according to general procedure B (b) using 1-iodopropane.1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-(1-propylpiperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrilewas prepared from tert-butyl3-(1-propylpiperidin-3-yl)azetidine-1-carboxylate using generalprocedures C and D using Precursor IV. The title compound was isolatedfrom its diastereomer by chiral SFC (AD-H, 40% isopropanol (0.1%diethylamine)/CO₂ 100 bars) as the first eluting peak. ¹H NMR (400 MHz,Methanol-d₄) δ 7.95 (s, 1H), 7.51-7.46 (m, 1H), 7.38 (d, J=8.5 Hz, 1H),7.35-7.28 (m, 1H), 6.45 (q, J=7.1 Hz, 1H), 4.32-4.22 (m, 2H), 4.02-3.86(m, 2H), 3.30-3.23 (m, 2H), 3.03-2.87 (m, 2H), 2.67-2.55 (m, 1H),2.42-2.28 (m, 2H), 2.06-1.94 (m, 1H), 1.90 (d, J=7.1 Hz, 3H), 1.88-1.65(m, 3H), 1.65-1.49 (m, 2H), 1.03-0.88 (m, 4H). LCMS [M+H] 498.0.

Example 73

1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-propylpiperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.tert-butyl 3-(1-propylpiperidin-3-yl)azetidine-1-carboxylate wasprepared according to general procedure B (b) using 1-iodopropane.1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-(1-propylpiperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrilewas prepared from tert-butyl3-(1-propylpiperidin-3-yl)azetidine-1-carboxylate using generalprocedures C and D using Precursor IV. The title compound was isolatedfrom its diastereomer by chiral SFC (AD-H, 40% isopropanol (0.1%diethylamine)/CO₂ 100 bars) as the second eluting peak. ¹H NMR (400 MHz,Methanol-d₄, free base): δ 7.95 (s, 1H), 7.49 (d, J=2.1 Hz, 1H), 7.38(d, J=8.5 Hz, 1H), 7.35-7.24 (m, 1H), 6.45 (q, J=7.0 Hz, 1H), 4.33-4.20(m, 2H), 4.02-3.84 (m, 2H), 3.39-3.19 (m, 2H), 3.02-2.89 (m, 2H),2.67-2.55 (m, 1H), 2.48-2.26 (m, 2H), 2.07-1.95 (m, 1H), 1.90 (d, J=7.1Hz, 3H), 1.88-1.65 (m, 2H), 1.65-1.45 (m, 3H), 0.98-0.87 (m, 4H). [LCMSM+H] 498.0.

Example 74

4-((S)-3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)-N,N-dimethylbutanamide.The diastereomeric mixture was prepared starting with general procedureA and methyl 4-oxobutanoate. tert-Butyl3-(1-(4-methoxy-4-oxobutyl)piperidin-3-yl)azetidine-1-carboxylate washydrolyzed with 4 equiv. of lithium hydroxide in methanol/water (3:1 byvolume) mixture at ambient temperature for 18 hours, followed byremoving methanol in vacuum, acidifying reaction mixture with conc. HCluntil pH 7 and extracting with DCM. Drying with sodium sulfate,filtering, and removing solvent in vacuum afforded the correspondingacid as white solid.4-(3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)butanoic acidwas mixed with HATU (1.2 equiv.) in anhydrous DMF (0.2M) and stirred for5 minutes, followed by the addition of diisopropylethylamine (3 equiv.)and additional 10 minutes of stirring at ambient temperature. 2Msolution of dimethylamine in THF was then added to the reaction mixture(5 equiv.), reaction was stirred at ambient temperature for 18 hours,quenched with 1M sodium carbonate, and extracted with ethyl acetate.Combined organic layer was dried over sodium sulfate, filtered, andconcentrated in vacuum. Crude material was deprotected using generalprocedure C, and final coupling with precursor IV using generalprocedure D. The title compound was separated from its diastereomer onan AD-H column using 35% isopropanol (0.1% diethylamine)/CO₂, 100 barsas the first peak. ¹H NMR (400 MHz, CD₃OD; free base): δ ppm 7.93 (s,1H), 7.47 (d, J=2.1 Hz, 1H), 7.38 (d, J=8.51 Hz, 1H), 7.31 (dd, J=2.1Hz, J=8.5 Hz, 1H), 6.45 (q, J=7.0 Hz, 1H), 4.21-4.31 (m, 2H), 3.92-4.02(m, 2H), 3.07 (m, 3H), 2.88-2.96 (m, 5H), 2.55-2.66 (m, 1H), 2.37-2.46(m, 4H), 1.94-2.04 (m, 1H), 1.90 (d, J=7.1 Hz, 3H), 152-1.88 (m, 7H),0.87-1.01 (m, 1H). LCMS [M+H]: 569.1.

Example 75

4-((R)-3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)-N,N-dimethylbutanamide.A mixture of the title compound and its diastereomer was prepared asdescribed in the previous example. The title compound was separated fromits diastereomer on an AD-H column using 35% isopropanol(0.1%diethylamine)/CO₂, 100 bar as the second eluting peak. ¹H NMR (400MHz, CD₃OD; free base): δ ppm 7.92 (s, 1H), 7.47 (d, J=2.1 Hz, 1H), 7.38(d, J=8.5 Hz, 1H), 7.31 (dd, J=2.1 Hz, J=8.5 Hz, 1H), 6.45 (q, J=7.1 Hz,1H), 4.21-4.31 (m, 2H), 3.92-4.02 (m, 2H), 3.06 (s, 3H), 2.88-2.96 (m,5H), 2.55-2.66 (m, 1H), 2.37-2.45 (m, 4H), 1.94-2.04 (m, 1H), 1.91 (d,J=7.1 Hz, 3H), 1.53-1.88 (m, 7H), 0.87-1.00 (m, 1H). LCMS [M+H]: 569.1.

Example 76

1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((S)-1-isopropylpiperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.A mixture of the title compound and its diastereomer was preparedaccording to general procedure A with acetone, general procedure C, andgeneral procedure D with precursor IV. The title compound was separatedfrom its diastereomer on an AD-H column using 30% isopropanol (0.1%diethylamine)/100bars CO₂ as the first eluting peak. ¹H NMR (400 MHz,CD₃OD; free base): δ ppm 7.94 (s, 1H), 7.47 (d, J=2.1 Hz, 1H), 7.38 (d,J=8.5 Hz, 1H), 7.31 (dd, J=2.1 Hz, J=8.5 Hz, 1H), 6.45 (q, J=7.0 Hz,1H), 4.23-4.33 (m, 2H), 3.92-4.02 (m, 2H), 2.84-2.94 (m, 2H), 2.74-2.84(m, 1H), 2.55-2.65 (m, 1H), 2.13-2.23 (m, 1H), 1.72-1.94 (m, 7H),1.52-1.66 (m, 1H), 1.07-1.20 (m, 7H), 0.85-0.98 (m, 1H). LCMS [M+H]:498.2.

Example 77

1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-isopropylpiperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.A mixture of the title compound and its diastereomer was preparedaccording to general procedure A with acetone, general procedure C, andgeneral procedure D with precursor IV. The title compound was separatedfrom its diastereomer on an AD-H column using 30% isopropanol (0.1%diethylamine)/100bars CO₂ as the second eluting peak. ¹11 NMR (400 MHz,CD₃OD; free base): δ ppm 7.94 (s, 1H), 7.48 (d, J=2.1 Hz, 1H), 7.39 (d,J=8.5 Hz, 1H), 7.31 (dd, J=2.1 Hz, J=8.5 Hz, 1H), 6.45 (q, J=7.1 Hz,1H), 4.22-4.32 (m, 2H), 3.92-4.02 (m, 2H), 2.84-2.94 (m, 2H), 2.73-2.83(m, 1H), 2.55-2.66 (m, 1H), 2.12-2.22 (m, 1H), 1.72-1.94 (m, 7H),1.52-1.66 (m, 1H), 1.07-1.21 (m, 7H), 0.85-0.98 (m, 1H). LCMS [M+H]:498.2.

Example 78

4-((R)-3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)butanamide.A mixture of the title compound and its diastereomer was preparedstarting with general procedure A and methyl 4-oxobutanoate. tert-Butyl3-(1-(4-methoxy-4-oxobutyl)piperidin-3-yl)azetidine-1-carboxylate washydrolyzed with 4 equiv. of lithium hydroxide in methanol/water (3:1 byvolume) mixture at ambient temperature for 18 hours, followed byremoving methnol in vacuum, acidifying reaction mixture with conc. HCluntil pH 7 and extracting with DCM. Drying with sodium sulfate,filtering, and removing solvent in vacuum afforded the correspondingacid as white solid.4-(3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)butanoic acidwas mixed with HATU (1.2 equiv.) in anhydrous DMF (0.2M) and stirred for5 minutes, followed by the addition of diisopropylethylamine (3 equiv.)and additional 10 minutes of stirring at ambient temperature. 2Msolution of dimethylamine in THF was then added to the reaction mixture(5 equiv.), reaction was stirred at ambient temperature for 18 hours,quenched with 1M sodium carbonate, and extracted with ethyl acetate.Combined organic layer was dried over sodium sulfate, filtered, andconcentrated in vacuum. Crude material was deprotected using procedureC, and final coupling with precursor IV using general procedure D. Thetitle compound was separated from its diastereomer on an AD-H columnusing 30% ethanol (0.1% diethylamine)/CO₂, 100 bars as the secondeluting peak. ¹H NMR (400 MHz, CD₃OD; free base): δ ppm 7.92 (s, 1H),7.47 (d, J=2.1 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.30 (dd, J=2.1 Hz,J=8.5 Hz, 1H), 6.44 (q, J=7.1 Hz, 1H), 4.21-4.31 (m, 2H), 3.92-4.02 (m,2H), 2.87-2.96 (m, 2H), 2.55-2.68 (m, 1H), 2.37-2.44 (m, 2H), 2.23 (t,J=7.4 Hz, 2H), 1.94-2.06 (m, 1H), 1.90 (d, J=7.1 Hz, 3H), 1.53-1.89 (m,7H), 0.87-1.00 (m, 1H). LCMS [M+H]: 541.2.

Example 79

4(S)-3-(1-(3-cyano-1-(R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)butanamide.A mixture of the title compound and its diastereomer was prepared asshown in previous example. The title compound was separated from itsdiastereomer on an AD-H column using 30% ethanol (0.1%diethylamine)/CO₂, 100 bars as the first eluting peak. ¹H NMR (400 MHz,CD₃OD; free base): δ ppm 7.93 (s, 1H), 7.47 (d, J=2.1 Hz, 1H), 7.38 (d,J=8.5 Hz, 1H), 7.31 (dd, J=2.1 Hz, J=8.5 Hz, 1H), 6.45 (q, J=7.1 Hz,1H), 4.22-4.32 (m, 2H), 3.92-4.02 (m, 2H), 2.88-2.98 (m, 2H), 2.55-2.68(m, 1H), 2.37-2.45 (m, 2H), 2.23 (t, J=7.4 Hz, 2H), 1.95-2.06 (m, 1H),1.90 (d, J=7.1 Hz, 3H), 1.53-1.99 (m, 7H), 0.84-1.01 (m, 1H). LCMS[M+H]: 541.2.

Example 80

6-(3-((R)-1-((1H-imidazol-2-yl)methyl)piperidin-3-yl)azetidin-1-yl)-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.A mixture of the title compound and its diastereomer was preparedstarting with general procedure A and 1H-imidazole-2-carbaldehyde,followed by general procedure C, and final coupling with precursor IVusing general procedure D. The title compound was separated from itsdiastereomer on an AD-H column using 20% ethanol (0.1%diethylamine)/CO₂, 100 bars as the second eluting peak. ^(l)EINIVIR (400MHz, CD₃OD; free base): δ ppm 7.89 (s, 1H), 7.46 (d, J=2.1 Hz, 1H), 7.37(d, J=8.5 Hz, 1H), 7.29 (dd, J=2.1 Hz, J=8.5 Hz, 1H), 7.00 (bs, 2H),6.43 (q, J=7.0 Hz, 1H), 4.16-4.30 (m, 2H), 3.85-3.98 (m, 2H), 3.62 (bs,2H), 2.76-2.88 (m, 2H), 2.58-2.70 (m, 1H), 2.06-2.16 (m, 1H), 1.52-1.94(m, 8H), 0.85-1.00 (m, 1H). LCMS [M+H]: 536.0.

Example 81

6-(3-((S)-14(1H-imidazol-2-yl)methyl)piperidin-3-yl)azetidin-1-yl)-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.A mixture of the title compound and its diastereomer was preparedstarting with general procedure A and 1H-imidazole-2-carbaldehyde,followed by general procedure C, and final coupling with precursor IVusing general procedure D. The title compound was separated from itsdiastereomer on an AD-H column using 20% ethanol (0.1%diethylamine)/CO₂, 100 bars as the first eluting peak. ¹H NMR (400 MHz,CD₃OD; free base): δ ppm 7.92 (s, 1H), 7.47 (d, J=2.1 Hz, 1H), 7.37 (d,J=8.5 Hz, 1H), 7.30 (dd, J=2.1 Hz, J=8.5 Hz, 1H), 7.00 (bs, 2H), 6.44(q, J=7.1 Hz, 1H), 4.18-4.32 (m, 2H), 3.82-4.00 (m, 2H), 3.63 (bs, 2H),2.77-2.89 (m, 2H), 2.58-2.70 (m, 1H), 2.04-2.14 (m, 1H), 1.53-1.94 (m,8H), 0.86-1.00 (m, 1H). LCMS [M+H]: 536.0.

Example 82

1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-((R)-4-hydroxybutan-2-yl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrileand1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-((S)-4-hydroxybutan-2-yl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.A mixture of the two titled compounds and their respective diastereomers(four diastereomers) was prepared using general procedure A with4-hydroxybutan-2-one, followed by general procedure C, and couplingusing general procedure D and precursor IV. Single diastereomers wereseparated on an AD-H column using 35% isopropanol (0.1%diethylamine)/CO₂, 100 bars and the compounds corresponding to peaks 1and 2 were then additionally purified on an OJ-H column using 20%isopropanol (0.1% diethylamine)/CO₂, 100 bars. The first eluting isomerhad the following ¹H NMR (400 MHz, CDCl₃; free base): δ ppm 7.61 (s,1H), 7.37 (s, 1H), 7.36 (d, J=5.9 Hz, 1H), 7.20 (dd, J=2.1 Hz, J=8.5 Hz,1H), 6.46 (q, J=7.1 Hz, 1H), 4.20-4.30 (m, 2H), 3.76-4.03 (m, 4H),2.86-3.02 (m, 2H), 2.70-2.80 (m, 1H), 2.47-2.68 (m, 2H), 1.87-1.98 (m,4H), 1.70-1.84 (m, 4H), 1.54-1.70 (m, 1H), 1.29-1.38 (m, 1H), 0.87-1.04(m, 4H). LCMS [M+H]: 528.2. The second eluting isomer had the following¹H NMR (400 MHz, CD₃OD; free base): δ ppm 7.82 (s, 1H), 7.37 (s, 1H),7.36 (d, J=6. Hz, 1H), 7.20 (dd, J=2.2 Hz, J=8.5 Hz, 1H), 6.46 (q, J=7.0Hz, 1H), 4.19-4.29 (m, 2H), 3.72-4.00 (m, 4H), 2.87-3.00 (m, 2H),2.70-2.80 (m, 1H), 2.52-2.64 (m, 1H), 2.14-2.24 (m, 1H), 1.98-2.10 (m,1H), 1.72-1.97 (m, 8H), 1.41-1.54 (m, 1H), 1.27-1.37 (m, 1H), 0.84-1.02(m, 4H). LCMS [M+H]: 528.2.

Example 83

1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((S)-1-((R)-4-hydroxybutan-2-yl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrileand1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((S)-1-((S)-4-hydroxybutan-2-yl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.A mixture of the two titled compounds and their respective diastereomers(four diastereomers) was prepared using general procedure A with4-hydroxybutan-2-one, followed by general procedure C, and couplingusing general procedure D and precursor IV. Single diastereomers wereseparated on an AD-H column using 35% isopropanol (0.1%diethylamine)/CO₂, 100 bars. The third eluting isomer had the following¹H NMR (400 MHz, CDCl₃; free base): δ ppm 7.82 (s, 1H), 7.34-7.37 (m,2H), 7.19 (dd, J=2.2 Hz, J=8.5 Hz, 1H), 6.45 (q, J=7.0 Hz, 1H),4.19-4.27 (m, 2H), 3.73-4.06 (m, 4H), 2.88-3.00 (m, 2H), 2.70-2.78 (m,1H), 2.53-2.66 (m, 1H), 2.15-2.25 (m, 1H), 2.00-2.10 (m, 1H), 1.72-1.98(m, 8H), 1.40-1.54 (m, 1H), 1.28-1.37 (m, 1H), 0.84-1.01 (m, 4H). LCMS[M+H]: 528.2. The fourth eluting isomer had the following ¹H NMR (400MHz, CDCl₃; free base): δ ppm 7.81 (s, 1H), 7.38 (d, J=2.1 Hz, 1H), 7.35(d, J=8.4 Hz, 1H), 7.19 (dd, J=2.2 Hz, J=8.4 Hz, 1H), 6.44 (q, J=7.2 Hz,1H), 4.18-4.29 (m, 2H), 3.68-4.08 (m, 4H), 2.86-3.00 (m, 2H), 2.46-2.78(m, 3H), 1.54-1.98 (m, 10H), 1.28-1.41 (m, 1H), 0.87-1.04 (m, 4H). LCMS[M+H]: 528.2.

Example 84

Methyl(2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)carbamate.A mixture of the title compound and its diastereomer was prepared usinggeneral procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followedby removal of phthaloyl group with hydrazine hydrate (4 equiv.) inmethanol (0.4M) at ambient temperature for 18 hours. The reactionmixture was diluted with water, extracted with DCM, organic layer wasdried over sodium sulfate, filtered and concentrated in vacuum. Thecrude material was dissolved in DCM (0.26M) and 3 equiv. oftriethylamine was added, followed by methylchloroformate (1.2 equiv.)dropwise at ambient temperature. Reaction mixture was stirred for 70minutes, quenched with 1M sodium carbonate, and extracted with ethylacetate. Organic phase was dried over sodium sulfate, filtered, andsolvent was removed in vacuum. Crude material was deprotected usinggeneral procedure C, and coupled with precursor II using generalprocedure D. The title compound was separated from its diastereomer onan AD-H column using 35% isopropanol (0.1% diethylamine)/CO₂, 100 barsas the first eluting peak. ¹H NMR (400 MHz, CD₃OD; free base): δ ppm7.75 (s, 1H), 7.45 (d, J=2.1 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H), 7.26 (dd,

J=2.1 Hz, J=8.5 Hz, 1H), 6.29 (q, J=7.2 Hz, 1H), 4.22-4.32 (m, 2H),3.94-4.04 (m, 2H), 3.43-3.69 (m, 7H), 3.12-3.22 (m, 2H), 2.80-2.92 (m,1H), 2.56-2.72 (m, 2H), 2.50 (s, 3H), 1.75-2.16 (m, 7H), 1.12-1.30 (m,1H). LCMS [M+H]: 546.1.

Example 85

Methyl(2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)carbamate.A mixture of the title compound and its diastereomer was prepared asshown in the previous example. The title compound was separated from itsdiastereomer on an AD-H column using 35% isopropanol (0.1%diethylamine)/CO₂, 100 bars as the second eluting peak. ¹H NMR (400 MHz,CD₃OD; free base): δ ppm 7.75 (s, 1H), 7.44 (d, J=2.1 Hz, 1H), 7.36 (d,J=8.5 Hz, 1H), 7.26 (dd, J=2.2 Hz, J=8.5 Hz, 1H), 6.29 (q, J=7.0 Hz,1H), 4.24-4.32 (m, 2H), 3.95-4.05 (m, 2H), 3.61-3.77 (m, 5H), 3.44-3.60(m, 2H), 3.21-3.29 (m, 2H), 2.88-2.98 (m, 1H), 2.62-2.73 (m, 2H), 2.50(s, 3H), 1.92-2.18 (m, 3H), 1.76-1.92 (m, 4H), 1.14-1.30 (m, 1H). LCMS[M+H]: 546.1.

Example 86

N-(2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)acetamide.A mixture of the title compound and its diastereomer was prepared usinggeneral procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followedby removal of phthaloyl group with hydrazine hydrate (4 equiv.) inmethanol (0.4M) at ambient temperature for 18 hours. The reactionmixture was diluted with water, extracted with DCM, organic layer wasdried over sodium sulfate, filtered and concentrated in vacuum. Thecrude material was dissolved in DCM (0.23M) and 3 equiv. oftriethylamine was added, followed by acetic anhydride (1.1 equiv.)dropwise at ambient temperature. Reaction mixture was stirred for 12hours, quenched with water, and extracted with DCM, dried over sodiumsulfate, filtered, and concentrated in vacuum. Crude material wasdeprotected using general procedure C, and coupled with precursor Vusing general procedure D. The title compound was separated from itsdiastereomer on an OD-H column using 20% methanol (0.1%diethylamine)/CO₂, 100 bars as the first eluting isomer. ¹H NMR (400MHz, CD₃OD; free base): δ ppm 7.94 (s, 1H), 7.47 (d, J=2.0 Hz, 1H),7.27-7.37 (m, 2H), 6.44 (q, J=7.0 Hz, 1H), 4.27-4.37 (m, 2H), 4.00-4.10(m, 2H), 3.50-3.78 (m, 5H), 3.23-3.29 (m, 2H), 2.87-2.98 (m, 1H),2.63-2.73 (m, 1H), 1.78-2.20 (m, 10H), 1.14-1.30 (m, 1H). LCMS [M+H]:584.0.

Example 87

N-(2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)acetamide.A mixture of the title compound and its diastereomer was prepared asshown in previous example. The title compound was separated from itsdiastereomer on an OD-H column using 20% methanol (0.1%diethylamine)/CO₂, 100 bars as the second eluting isomer. ¹H NMR (400MHz, CD₃OD; free base): δ ppm 7.93 (s, 1H), 7.48 (d, J=2.1 Hz, 1H),7.28-7.38 (m, 2H), 6.44 (q, J=7.1 Hz, 1H), 4.26-4.37 (m, 2H), 3.98-4.08(m, 2H), 3.44-3.64 (m, 4H), 3.06-3.16 (m, 2H), 2.63-2.88 (m, 2H),2.46-2.60 (m, 1H), 1.72-2.16 (m, 9H), 1.12-1.26 (m, 1H). LCMS [M+H]:584.0.

Example 88

N-(2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)isobutyramide.A mixture of the title compound and its diastereomer was prepared usinggeneral procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanol, followedby removal of phthaloyl group with hydrazine hydrate (4 equiv.) inmethanol (0.4M) at ambient temperature for 18 hours. The reactionmixture was diluted with water, extracted with DCM (3×10mL), and theorganic layer was dried over sodium sulfate, filtered and concentratedin vacuum. The crude material was dissolved in DMF (0.5M) and 3 equiv.of triethylamine and 1.2 equiv. of HATU was added and stirred for 15minutes. Solution of isobutyric acid in DCM was added and the reactionmixture was stirred at ambient temperature. As soon as reaction wascomplete it was quenched by 1M sodium carbonate, extracted 3 times withethylacetate, dried with sodium sulfate, filtered, and concentrated invacuum. Crude material was deprotected using general procedure C, andcoupled with precursor V using general procedure D. The title compoundwas separated from its diastereomer on an AS-H column using 25%isopropanol (0.1% diethylamine)/CO₂, 100 bars as the second elutingisomer. ¹H NMR (400 MHz, CD₃OD; free base): δ ppm 7.93 (s, 1H), 7.48 (d,J=2.0 Hz, 1H), 7.28-7.36 (m, 2H), 6.44 (q, J=7.1 Hz, 1H), 4.28-4.38 (m,2H), 3.99-4.10 (m, 2H), 3.50-3.68 (m, 4H), 3.17-3.27 (m, 2H), 2.84-3.00(bm, 1H), 2.62-2.78 (bm, 2H), 2.43-2.55 (m, 1H), 1.76-2.22 (m, 7H),1.11-1.34 (m, 7H). LCMS [M+H]: 612.2.

Example 89

N-(2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)isobutyramide.A mixture of the title compound and its diastereomer was prepared asshown in previous example. The title compound was separated from itsdiastereomer on an AS-H column using 25% isopropanol (0.1%diethylamine)/CO₂, 100 bars as the first eluting isomer. ¹H NMR (400MHz, CD₃OD; free base): δ ppm 7.93 (s, 1H) ppm 7.48 (d, J=2.1 Hz, 1H),7.28-7.37 (m, 2H), 6.44 (q, J=7.1 Hz, 1H), 4.24-4.37 (m, 2H), 3.98-4.08(m, 2H), 3.40-3.60 (m, 4H), 3.03-3.16 (m, 2H), 2.63-2.87 (bm, 2H),2.41-2.60 (m, 2H), 1.72-2,15 (m, 7H), 1.11-1.25 (m, 7H). LCMS [M+H]:612.2.

Example 90

N-(2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)isobutyramide.A mixture of the title compound and its diastereomer was prepared usinggeneral procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanol, followedby removal of phthaloyl group with hydrazine hydrate (4 equiv.) inmethanol (0.4M) at ambient temperature for 18 hours. The reactionmixture was diluted with water, extracted with DCM (3×10mL), organiclayer was dried over sodium sulfate, filtered and concentrated invacuum. The crude material was dissolved in DMF (0.5M) and 3 equiv. oftriethylamine and 1.2 equiv. of HATU was added and stirred for 15minutes. Solution of isobutyric acid in DCM was added and the reactionmixture was stirred at ambient temperature. As soon as reaction wascomplete it was quenched by 1M sodium carbonate, extracted 3 times withethylacetate, dried with sodium sulfate, filtered, and concentrated invacuum. Crude material was deprotected using general procedure C, andcoupled with precursor II using general procedure D. The title compoundwas separated from its diastereomer on an AD-H column using 25% ethanol(0.1% diethylamine)/CO₂, 100 bars as the first eluting isomer. ¹H NMR(400 MHz, CD₃OD; free base): δ ppm 7.75 (s, 1H), 7.45 (d, J=2.1 Hz, 1H),7.36 (d, J=8.5 Hz, 1H), 7.26 (dd, J=2.2 Hz, J=8.5 Hz, 1H), 6.29 (q,J=7.1 Hz, 1H), 4.22-4.33 (m, 2H), 3.95-4.05 (m, 2H), 3.53-3.73 (m, 4H),3.21-3.31 (m, 2H), 2.89-3.00 (m, 1H), 2.62-2.78 (m, 2H), 2.45-2.52 (m,4H), 1.80-2.20 (m, 7H), 1.09-1.16 (m, 7H). LCMS [M+H]: 558.1.

Example 91

N-(2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)isobutyramide.A mixture of the title compound and its diastereomer was prepared asshown in previous example. The title compound was separated from itsdiastereomer on an AD-H column using 25% ethanol (0.1%diethylamine)/CO₂, 100 bars as the second eluting isomer. ¹H NMR (400MHz, CD₃OD; free base): δ ppm 7.76 (s, 1H), 7.44 (d, J=2.1 Hz, 1H), 7.35(d, J=8.5 Hz, 1H), 7.26 (dd, J=2.1 Hz, J=8.5 Hz, 1H), 6.29 (q, J=7.1 Hz,1H), 4.23-4.33 (m, 2H), 3.96-4.05 (m, 2H), 3.50-3.70 (m, 5H), 3.22-3.28(m, 2H), 2.90-3.00 (m, 1H), 2.62-2.72 (m, 1H), 2.43-2.53 (m, 4H),1.77-2.20 (m, 7H), 1.08-1.30 (m, 7H). LCMS [M+H]: 558.1.

Example 92

N-(2-((R)-3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)acetamide.A mixture of the title compound and its diastereomer was prepared usinggeneral procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanol, followedby removal of phthaloyl group with hydrazine hydrate (4 equiv.) inmethanol (0.4M) at ambient temperature for 18 hours. The reactionmixture was diluted with water, extracted with DCM, organic layer wasdried over sodium sulfate, filtered and concentrated in vacuum. Thecrude material was dissolved in DCM (0.23M) and 3 equiv. oftriethylamine was added, followed by acetic anhydride (1.1 equiv.)dropwise at ambient temperature. Reaction mixture was stirred for 12hours, quenched with water, and extracted with DCM, dried over sodiumsulfate, filtered, and concentrated in vacuum. Crude material wasdeprotected using general procedure C, and coupled with precursor IVusing general procedure D. The title compound was separated from itsdiastereomer on an AD-H column using 40% ethanol (0.1%diethylamine)/CO₂, 100 bars as the first eluting isomer. ¹H NMR (400MHz, CD₃OD; free base): δ ppm 7.91 (s, 1H), 7.46 (d, J=2.1 Hz, 1H), 7.37(d, J=8.5 Hz, 1H), 7.30 (dd, J=2.1 Hz, J=8.4 Hz, 1H), 6.44 (q, J=7.1 Hz,1H), 4.20-4.30 (m, 2H), 3.92-4.02 (m, 2H), 3.34 (t, J=7.0 Hz, 2H),2.88-2.98 (m, 2H), 2.55-2.67 (m, 1H), 2.45-2.53 (m, 2H), 1.53-2.08 (m,12H), 0.87-1.01 (m, 1H). LCMS [M+H] 541.1.

Example 93

N-(2-((S)-3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)acetamide.A mixture of the title compound and its diastereomer was prepared usinggeneral procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followedby removal of phthaloyl group with hydrazine hydrate (4 equiv.) inmethanol (0.4M) at ambient temperature for 18 hours. The reactionmixture was diluted with water, extracted with

DCM, organic layer was dried over sodium sulfate, filtered andconcentrated in vacuum. The crude material was dissolved in DCM (0.23M)and 3 equiv. of triethylamine was added, followed by acetic anhydride(1.1 equiv.) dropwise at ambient temperature. Reaction mixture wasstirred for 12 hours, quenched with water, and extracted with DCM, driedover sodium sulfate, filtered, and concentrated in vacuum. Crudematerial was deprotected using general procedure C, and coupled withprecursor IV using general procedure D. The title compound was separatedfrom its diastereomer on an AD-H column using 40% ethanol (0.1%diethylamine)/CO₂, 100 bars as the second eluting isomer. ¹H NMR (400MHz, CD₃OD; free base): δ ppm 7.92 (s, 1H), 7.46 (d, J=2.1 Hz, 1H), 7.37(d, J=8.5 Hz, 1H), 7.30 (dd, J=2.1 Hz, J=8.5 Hz, 1H), 6.44 (q, J=7.1 Hz,1H), 4.20-4.30 (m, 2H), 3.91-4.02 (m, 2H), 3.30-3.38 (m, 2H), 2.87-3.87(m, 2H), 2.55-2.67 (m, 1H), 2.45-2.53 (m, 2H), 1.52-2.10 (m, 12H),0.86-1.00 (m, 1H). LCMS [M+H] 541.1.

Example 94

1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((S)-1-(3-hydroxypropyl)pyrrolidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.A mixture of the title compound and its diastereomer was prepared usingcommercially available tert-butyl3-(1-(2-hydroxyethyl)pyrrolidin-3-yl)azetidine-1-carboxylate instead oftert-butyl 3-(piperidin-3-yl)azetidine-1-carboxylate in generalprocedure A. Followed by deprotection using general procedure C andcoupling with precursor IV according to the general procedure D. In allof these general procedures the corresponding pyrrolidine analog wasused. The title compound was separated from its diastereomer on an OJ-Hcolumn with 20% methanol (0.1% diethylamine)/CO₂, 100 bars as the firsteluting isomer. ¹H NMR (400 MHz, CDCl₃; free base): δ ppm 7.81 (s, 1H),7.34-7.38 (m, 2H), 7.19 (dd, J=2.2 Hz, J=8.5 Hz, 1H), 6.45 (q, J=7.1 Hz,1H), 4.22-4.30 (m, 2H), 3.77-3.87 (m, 4H), 2.72-2.88 (m, 5H), 2.60-2.70(m, 1H), 2.49-2.60 (m, 1H), 2.42-2.49 (m, 1H), 2.03-2.13 (m, 1H), 1.89(d, J=7.1 Hz, 3H), 1.70-1.79 (m, 2H), 1.42-1.53 (m, 1H). LCMS [M+H]500.0.

Example 95

1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-(3-hydroxypropyl)pyrrolidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.A mixture of the title compound and its diastereomer was prepared usingcommercially available tert-butyl3-(1-(2-hydroxyethyl)pyrrolidin-3-yl)azetidine-1-carboxylate instead oftert-butyl 3-(piperidin-3-yl)azetidine-1-carboxylate in generalprocedure A. Followed by deprotection using general procedure C andcoupling with precursor IV according to the general procedure D. In allof these general procedures the corresponding pyrrolidine analog wasused. The title compound was separated from its diastereomer on an OJ-Hcolumn with 20% methanol (0.1% diethylamine)/CO₂, 100 bars as the secondeluting isomer. ¹H NMR (400 MHz, CDCl₃; free base): δ ppm 7.81 (s, 1H),7.34-7.38 (m, 2H), 7.19 (dd, J=2.1 Hz, J=8.5 Hz, 1H), 6.45 (q, J=7.1 Hz,1H), 4.20-4.30 (m, 2H), 3.77-3.88 (m, 4H), 2.72-2.88 (m, 5H), 2.60-2.70(m, 1H), 2.48-2.60 (m, 1H), 2.41-2.48 (m, 1H), 2.02-2.13 (m, 1H), 1.89(d, J=7.1 Hz, 3H), 1.70-1.78 (m, 2H), 1.42-1.53 (m, 1H). LCMS [M+H]500.0.

Example 96

N-(2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)propane-2-sulfonamide.A mixture of the title compound and its diastereomer was prepared usinggeneral procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followedby removal of phthaloyl group with hydrazine hydrate (4 equiv.) inmethanol (0.4M) at ambient temperature for 18 hours. The reactionmixture was diluted with water, extracted with DCM, organic layer wasdried over sodium sulfate, filtered and concentrated in vacuum. Thecrude tert-butyl 3-[1-(2-aminoethyl)-3-piperidyl]azetidine-1-carboxylate(120 mg, 0.423 mmol) in DCM (2 mL) was treated with triethylamine (129mg, 1.27 mmol, 3.0 equiv.) and 2-propanesulfonyl chloride (73 mg, 0.51mmol, 1.2 equiv). After 30 min, the mixture was quenched with 1M aq.sodium carbonate (10 mL) and extracted with ethyl acetate (3×10 mL). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo to afford tert-butyl3-(1-(2-((l-methylethyl)sulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylate.tert-Butyl3-(1-(2-((1-methylethyl)sulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylatewas then condensed with Precursor II according to general procedures Cand D to afford a mixture of diastereomers. The title compound wasseparated from its diastereomer by SFC using a AS-H 20×250 mm column andeluting with 25% isopropanol (0.1% diethylamine) in CO₂ to give the freebase of the title compound as the first eluting isomer and converted tothe corresponding HCl salt by dissolution in EtOH, cooling to 0° C., andaddition of 1 equiv. of 0.01M HCl in EtOH. ¹H NMR (400 MHz, Methanol-d₄;HCl Salt) δ 7.74 (s, 1H), 7.43 (d, J=2.1 Hz, 1H), 7.36 (d, J=8.5 Hz,1H), 7.26 (dd, J=8.5, 2.2 Hz, 1H), 6.28 (q, J=7.1 Hz, 1H), 4.26 (q,J=8.6 Hz, 2H), 4.04-3.94 (m, 2H), 3.77-3.69 (m, 1H), 3.68-3.61 (m, 1H),3.57-3.46 (m, 2H), 3.37-3.32 (m, 1H), 3.29-3.21 (m, 2H), 3.02-2.92 (m,1H), 2.75-2.61 (m, 2H), 2.50 (s, 3H), 2.20-2.09 (m, 1H), 2.07-1.88 (m,3H), 1.86 (d, J=7.1 Hz, 3H), 1.37 (d, J=6.8, Hz, 3H), 1.36 (d, J=6.8,Hz, 3H), 1.27-1.20 (m, 1H). LCMS [M+H] 594.1.

Example 97

N-(2-((S)-3-(1-(1-((R)-1-(2,4-di chl orophenyl)ethyl)-3-m ethyl-1H-pyrazol o[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)propane-2-sulfonamide.A mixture of the title compound and its diastereomer was prepared usinggeneral procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followedby removal of phthaloyl group with hydrazine hydrate (4 equiv.) inmethanol (0.4M) at ambient temperature for 18 hours. The reactionmixture was diluted with water, extracted with DCM, organic layer wasdried over sodium sulfate, filtered and concentrated in vacuum. Thecrude tert-butyl 3-[1-(2-aminoethyl)-3-piperidyl]azetidine-1-carboxylate(120 mg, 0.423 mmol) in DCM (2 mL) was treated with triethylamine (129mg, 1.27 mmol, 3.0 equiv.) and 2-propanesulfonyl chloride (73 mg, 0.51mmol, 1.2 equiv). After 30 min, the mixture was quenched with 1M aq.

sodium carbonate (10 mL) and extracted with ethyl acetate (3×10 mL). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo to afford tert-butyl 3-(1-(2-((1-methylethyl)sulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylate.tert-Butyl3-(1-(2-((1-methylethyl)sulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylatewas then condensed with Precursor II according to general procedures Cand D to afford a mixture of diastereomers. The title compound wasseparated from its diastereomer by SFC using a AS-H 20×250 mm column andeluting with 25% isopropanol (0.1% diethylamine) in CO₂ to give the freebase of the title compound as the second eluting isomer and converted tothe corresponding HCl salt by dissolution in EtOH, cooling to 0° C., andaddition of 1 equiv. of 0.01M HCl in EtOH. ¹H NMR (400 MHz, Methanol-d₄;HCl Salt) δ 7.74 (s, 1H), 7.44 (d, J=2.1 Hz, 1H), 7.37 (d, J=8.5 Hz,1H), 7.26 (dd, J=8.5, 2.1 Hz, 1H), 6.29 (q, J=7.1 Hz, 1H), 4.33-4.22 (m,2H), 4.04-3.96 (m, 2H), 3.77-3.70 (m, 1H), 3.68-3.59 (m, 1H), 3.56-3.45(m, 2H), 3.37-3.32 (m, 1H), 3.27-3.23 (m, 2H), 3.01-2.91 (m, 2H),2.74-2.62 (m, 2H), 2.50 (s, 3H), 2.19-2.10 (m, 1H), 2.08-1.88 (m, 2H),1.86 (d, J=7.1 Hz, 3H), 1.37 (d, J=6.8 Hz, 3H), 1.35 (d, J=6.8 Hz, 3H),1.24-1.18 (m, 1H). LCMS [M+H] 594.0.

Example 98

N-(2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)methanesulfonamide.A mixture of the title compound and its diastereomer was prepared usinggeneral procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followedby removal of phthaloyl group with hydrazine hydrate (4 equiv.) inmethanol (0.4M) at ambient temperature for 18 hours. The reactionmixture was diluted with water, extracted with DCM, organic layer wasdried over sodium sulfate, filtered and concentrated in vacuum. Thecrude tert-butyl 3-[1-(2-aminoethyl)-3-piperidyl]azetidine-1-carboxylate(120 mg, 0.423 mmol) in DCM (2 mL) was treated with triethylamine (129mg, 1.27 mmol, 3.0 equiv.) and methanesulfonyl chloride (58 mg, 0.51mmol, 1.2 equiv). After 30 min, the mixture was quenched with 1M aq.sodium carbonate (10 mL) and extracted with ethyl acetate (3×10 mL). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo to afford tert-butyl3-(1-(2-(methylsulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylate.tert-Butyl3-(1-(2-(methylsulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylatewas then condensed with Precursor II according to general procedures Cand D to afford a mixture of diastereomers. The title compound wasseparated from its diastereomer by SFC using a AS-H column and elutingwith 30% ethanol (0.1% diethylamine) in CO₂ to give the free base of thetitle compound as the first eluting isomer and converted to thecorresponding HCl salt by dissolution in EtOH, cooling to 0° C., andaddition of 1 equiv. of 0.01M HCl in EtOH. ¹H NMR (400 MHz, Methanol-d₄,HCl Salt) δ 7.73 (s, 1H), 7.44 (d, J=2.1 Hz, 1H), 7.37 (d, J=8.5 Hz,1H), 7.26 (dd, J=8.5, 2.1 Hz, 1H), 6.29 (q, J=7.1 Hz, 1H), 4.32-4.19 (m,2H), 4.03-3.93 (m, 2H), 3.57-3.40 (m, 4H), 3.22-3.11 (m, 2H), 3.02 (s,3H), 2.88-2.75 (m, 1H), 2.72-2.47 (m, 2H), 2.50 (s, 3H), 2.17-2.03 (m,1H), 2.02-1.89 (m, 2H), 1.87 (d, J=7.1 Hz, 3H), 1.85-1.76 (m, 1H),1.25-1.08 (m, 1H). LCMS [M+H] 566.0 (M+H⁺).

Example 99

N-(2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)methanesulfonamide.A mixture of the title compound and its diastereomer was prepared usinggeneral procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followedby removal of phthaloyl group with hydrazine hydrate (4 equiv.) inmethanol (0.4M) at ambient temperature for 18 hours. The reactionmixture was diluted with water, extracted with DCM, organic layer wasdried over sodium sulfate, filtered and concentrated in vacuum. Thecrude tert-butyl 3-[1-(2-aminoethyl)-3-piperidyl]azetidine-1-carboxylate(120 mg, 0.423 mmol) in DCM (2 mL) was treated with triethylamine (129mg, 1.27 mmol, 3.0 equiv.) and methanesulfonyl chloride (58 mg, 0.51mmol, 1.2 equiv). After 30 min, the mixture was quenched with 1M aq.sodium carbonate (10 mL) and extracted with ethyl acetate (3×10 mL). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo to afford tert-butyl3-(1-(2-(methylsulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylate.tert-Butyl3-(1-(2-(methylsulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylatewas then condensed with Precursor II according to general procedures Cand D to afford a mixture of diastereomers. The title compound wasseparated from its diastereomer by SFC using a AS-H column and elutingwith 30% ethanol (0.1% diethylamine) in COto give the free base of thetitle compound as the second eluting isomer and converted to thecorresponding HCl salt by dissolution in EtOH, cooling to 0° C., andaddition of 1 equiv. of 0.01M HCl in EtOH. ¹H NMR (400 MHz, Methanol-d₄;HCl Salt) δ 7.76 (s, 1H), 7.45 (d, J=2.1 Hz, 1H), 7.37 (d, J=8.5 Hz,1H), 7.27 (dd, J=8.5, 2.1 Hz, 1H), 6.29 (q, J=7.1 Hz, 1H), 4.34-4.21 (m,2H), 4.04-3.96 (m, 2H), 3.82-3.41 (m, 4H), 3.29-3.26 (m, 1H), 3.03 (s,3H), 3.02-2.92 (m, 2H), 2.76-2.60 (m, 2H), 2.50 (s, 3H), 2.23-2.10 (m,1H), 2.08-1.89 (m, 3H), 1.87 (d, J=7.1 Hz, 3H), 1.25-1.18 (m, 1H). LCMS[M+H] 566.0.

Example 100

N-(2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)acetamide.A mixture of the title compound and its diastereomer was prepared usinggeneral procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followedby removal of phthaloyl group with hydrazine hydrate (4 equiv.) inmethanol (0.4M) at ambient temperature for 18 hours. The reactionmixture was diluted with water, extracted with DCM, organic layer wasdried over sodium sulfate, filtered and concentrated in vacuum. Thecrude tert-butyl 3-[1-(2-aminoethyl)-3-piperidyl]azetidine-1-carboxylate(120 mg, 0.423 mmol) in DCM (2 mL) was treated with triethylamine (129mg, 1.27 mmol, 3.0 equiv.) and acetyl chloride (40.0 mg, 0.51 mmol, 1.2equiv). After 30 min, the mixture was quenched with 1M aq. sodiumcarbonate (10 mL) and extracted with ethyl acetate (3×10 mL). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo to afford tert-butyl3-(1-(2-acetamidoethyl)piperidin-3-yl)azetidine-1-carboxylate.tert-butyl 3-(1-(2-acetamidoethyl)piperidin-3-yl)azetidine-1-carboxylatewas then condensed with Precursor II according to general procedures Cand D to afford a mixture of diastereomers. The title compound wasseparated from its diastereomer by SFC using an AD-H column and elutingwith 25% ethanol (0.1% diethylamine) in CO₂ to give the free base of thetitle compound as the first eluting isomer and converted to thecorresponding HCl salt by dissolution in EtOH, cooling to 0° C., andaddition of 1 equiv. of 0.01M HCl in EtOH. ¹H NMR (400 MHz, Methanol-d₄;HCl Salt) δ 7.75 (s, 1H), 7.44 (d, J=2.1 Hz, 1H), 7.36 (d, J=8.5 Hz,1H), 7.26 (dd, J=8.5, 2.1 Hz, 1H), 6.29 (q, J=7.1 Hz, 1H), 4.27 (q,J=8.9 Hz, 2H), 4.00 (ddd, J=11.6, 8.9, 5.6 Hz, 2H), 3.78-3.63 (m, 2H),3.58-3.46 (m, 1H), 3.25 (t, J=5.8 Hz, 2H), 2.98-2.86 (m, 1H), 2.73-2.62(m, 2H), 2.50 (s, 3H), 2.14-1.94 (m, 4H), 1.99 (s, 3H), 1.86 (d, J=7.1Hz, 3H), 1.86-1.77 (m, 1H), 1.21 (d, J=17.3 Hz, 1H). LCMS [M+H] 530.1.

Example 101

N-(2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)acetamide.A mixture of the title compound and its diastereomer was prepared usinggeneral procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followedby removal of phthaloyl group with hydrazine hydrate (4 equiv.) inmethanol (0.4M) at ambient temperature for 18 hours. The reactionmixture was diluted with water, extracted with DCM, organic layer wasdried over sodium sulfate, filtered and concentrated in vacuum. Thecrude tert-butyl 3-[1-(2-aminoethyl)-3-piperidyl]azetidine-1-carboxylate(120 mg, 0.423 mmol) in DCM (2 mL) was treated with triethylamine (129mg, 1.27 mmol, 3.0 equiv.) and acetyl chloride (40.0 mg, 0.51 mmol, 1.2equiv). After 30 min, the mixture was quenched with 1M aq. sodiumcarbonate (10 mL) and extracted with ethyl acetate (3×10 mL). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo to afford tert-butyl3-(1-(2-acetamidoethyl)piperidin-3-yl)azetidine-1-carboxylate.tert-butyl 3-(1-(2-acetamidoethyl)piperidin-3-yl)azetidine-1-carboxylatewas then condensed with Precursor II according to general procedures Cand D to afford a mixture of diastereomers. The title compound wasseparated from its diastereomer by SFC using an AD-H column and elutingwith 25% ethanol (0.1% diethylamine) in CO₂ to give the free base of thetitle compound as the second eluting isomer and converted to thecorresponding HCl salt by dissolution in EtOH, cooling to 0° C., andaddition of 1 equiv. of 0.01M HCl in EtOH. ¹H NMR (400 MHz, Methanol-d₄;HCl Salt) δ 7.75 (s, 1H), 7.44 (d, J=2.1 Hz, 1H), 7.36 (d, J=8.5 Hz,1H), 7.26 (dd, J=8.5, 2.2 Hz, 1H), 6.29 (q, J=7.1 Hz, 1H), 4.27 (t,J=8.3 Hz, 2H), 3.99 (ddd, J=8.5, 5.6, 2.2 Hz, 2H), 3.75-3.44 (m, 3H),3.21 (t, J=5.8 Hz, 2H), 2.99-2.81 (m, 1H), 2.77-2.57 (m, 2H), 2.50 (s,3H), 2.18-2.00 (m, 3H), 2.00 (s, 3H), 1.99-1.92 (m, 1H), 1.87 (d, J=7.1Hz, 3H), 1.81 (s, 1H), 1.27-1.18 (m, 1H). LCMS [M+H] 530.1.

Example 102

1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-isopropylpiperidin-3-yl)azetidin-1-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine.The title compound was prepared using general procedure A with PrecursorVI and acetone, followed by procedure C. The resulting product wascondensed with Precursor V using procedure D. ¹H NMR (400 MHz,Methanol-d₄; HCl Salt) δ 7.94 (s, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.35 (d,J=8.5 Hz, 1H), 7.31 (dd, J=8.5, 2.0 Hz, 1H), 6.44 (q, J=7.0 Hz, 1H),4.38-4.26 (m, 2H), 4.08-3.98 (m, 2H), 3.49-3.34 (m, 2H), 3.03-2.90 (m,1H), 2.82-2.63 (m, 2H), 2.21-2.13 (m, 2H), 2.11-2.03 (m, 1H), 2.02-1.95(m, 1H), 1.91 (d, J=7.1 Hz, 3H), 1.88-1.80 (m, 1H), 1.38 (d, J=4.5 Hz,6H), 1.26-1.20 (m, 1H). LCMS [M+H] 541.0.

Example 103

(R)-1-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propan-2-ol.Precursor VI (270 mg, 1.30 mmol) was condensed with(2R)-2-hydroxypropanoic acid (152 mg, 1.69 mmol) in DMF (5 mL) using1H-benzo[d][1,2,3]triazol-1-ol (258 mg, 1.69 mmol) and3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-aminehydrochloride (324 mg, 1.69 mmol) for 30 min and then poured into ethylacetate (50 mL), washed with brine (50mL), dried over sodium sulfate,filtered and concentrated under reduced pressure, the residue waspurified by flash chromatography using silica gel and a gradient ofmethanol (0 to 20%) in DCM to afford tert-butyl3-[(3R)-1-[(2R)-2-hydroxypropanoyl]-3-piperidyl]azetidine-1-carboxylate(350 mg, 1.12 mmol).3-[(3R)-1-[(2R)-2-hydroxypropanoyl]-3-piperidyl]azetidine-1-carboxylate(350 mg, 1.12 mmol) was dissolved in tetrahydrofuran (6 mL) and treatedwith borane-tetrahydrofuran complex (3.36 mL, 3.36 mmol, 1M intetrahydrofuran) and stirred for 12 hours, quenched with methanol andconcentrated under reduced pressure, the residue was purified by flashchromatography using silica gel and a gradient of methanol (0 to 20%) inDCM to afford tert-butyl3-[(3R)-1-[(2R)-2-hydroxypropyl]-3-piperidyl]azetidine-1-carboxylate(193 mg, 0.6500 mmol). tert-butyl3-[(3R)-1-[(2R)-2-hydroxypropyl]-3-piperidyl]azetidine-1-carboxylate wasthen condensed with Precursor V using general procedures C and D toafford the title compound. ¹H NMR (400 MHz, Methanol-d₄; HCl Salt) δ7.93 (s, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.35 (d, J=8.5 Hz, 1H), 7.30 (dd,J=8.5, 2.0 Hz, 1H), 6.44 (q, J=7.1 Hz, 1H), 4.38-4.26 (m, 2H), 4.26-4.17(m, 1H), 4.07-3.96 (m, 2H), 3.76-3.70 (m, 1H), 3.70-3.65 (m, 1H),3.58-3.54 (m, 1H), 3.15-3.00 (m, 2H), 2.93-2.81 (m, 1H), 2.79-2.58 (m,2H), 2.28-2.12 (m, 1H), 2.11-1.92 (m, 2H), 1.91 (d, J=7.1 Hz, 3H),1.89-1.75 (m, 1H), 1.24 (d, J=6.2 Hz, 3H), 1.22-1.18 (m, 1H). LCMS [M+H]557.0.

Example 104

(S)-1-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propan-2-ol.Precursor VI (270 mg, 1.30 mmol) was condensed with(2S)-2-hydroxypropanoic acid (152 mg, 1.69 mmol) in DMF (5 mL) using1H-benzo[d][1,2,3]triazol-1-ol (258 mg, 1.69 mmol) and3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-aminehydrochloride (324 mg, 1.69 mmol) for 30 min and then poured into ethylacetate (50 mL), washed with brine (50mL), dried over sodium sulfate,filtered and concentrated under reduced pressure, the residue waspurified by flash chromatography using silica gel and a gradient ofmethanol (0 to 20%) in DCM to afford tert-butyl3-[(3R)-1-[(25)-2-hydroxypropanoyl]-3-piperidyl]azetidine-1-carboxylate(350 mg, 1.12 mmol).3-[(3R)-1-[(25)-2-hydroxypropanoyl]-3-piperidyl]azetidine-1-carboxylate(350 mg, 1.12 mmol) was dissolved in tetrahydrofuran (6 mL) and treatedwith borane- tetrahydrofuran complex (3.36 mL, 3.36 mmol, 1M intetrahydrofuran) and stirred for 12 hours, quenched with methanol andconcentrated under reduced pressure, the residue was purified by flashchromatography using silica gel and a gradient of methanol (0 to 20%) inDCM to afford tert-butyl3-[(3R)-1-[(2S)-2-hydroxypropyl]-3-piperidyl]azetidine-1-carboxylate (90mg, 0.3016 mmol). tert-butyl3-[(3R)-1-[(2S)-2-hydroxypropyl]-3-piperidyl]azetidine-1-carboxylate wasthen condensed with Precursor V using general procedures C and D toafford the title compound. ¹H NMR (400 MHz, Methanol-d₄; HCl Salt) δ7.93 (s, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.35 (d, J=8.5 Hz, 1H), 7.30 (dd,J=8.5, 2.1 Hz, 1H), 6.44 (q, J=7.1 Hz, 1H), 4.37-4.25 (m, 2H), 4.23-4.10(m, 1H), 4.07-3.97 (m, 2H), 3.77-3.56 (m, 2H), 3.55-3.39 (m, 1H),3.07-2.76 (m, 3H), 2.19-2.03 (m, 1H), 1.98-1.92 (m, 2H), 1.91 (d, J=7.1Hz, 3H), 1.90-1.80 (m, 2H), 1.22 (d, J=6.2 Hz, 3H), 1.20-1.17 (m, 1H).LCMS [M+H] 557.0.

Example 105

N—((R)-1-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propan-2-yl)acetamide.Precursor VI (270 mg, 1.13 mmol) was condensed with(2R)-2-(benzyloxycarbonylamino)propanoic acid (376.7 mg, 1.69 mmol) inDIVIF (3 mL) using2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (642 mg, 1.69 mmol) and N,N-Diisopropylethylamine(0.587 mL, 3.38 mmol) for 12 hours and then poured into ethyl acetate(50 mL), washed with brine (50mL), dried over sodium sulfate, filteredand concentrated under reduced pressure, the residue was purified byflash chromatography using silica gel and a gradient of ethyl acetate(10 to 100%) in hexanes to afford tert-butyl3-[(3R)-1-[(2R)-2-(benzyloxycarbonylamino)propanoyl]-3-piperidyl]azetidine-1-carboxylate(306 mg, 0.687 mmol). tert-butyl3-[(3R)-1-[(2R)-2-(benzyloxycarbonylamino)propanoyl]-3-piperidyl]azetidine-1-carboxylate(306 mg, 0.687 mmol) was dissolved in tetrahydrofuran (6 mL) and treatedwith borane-tetrahydrofuran complex (2.06 mL, 2.06 mmol, 1M intetrahydrofuran) and stirred for 12 hours, quenched with methanol andconcentrated under reduced pressure, the residue was purified by flashchromatography using silica gel and a gradient of methanol (0 to 20%) inDCM to afford tert-butyl3-[(3R)-1-[(2R)-2-(benzyloxycarbonylamino)propyl]-3-piperidyl]azetidine-1-carboxylate(296 mg, 0.687 mmol). tert-butyl3-[(3R)-1-[(2R)-2-(benzyloxycarbonylamino)propyl]-3-piperidyl]azetidine-1-carboxylate(296 mg, 0.687 mmol) was dissolved in methanol (5mL) and palladium oncarbon 10 wt.% (89.4 mg) was added, the mixture was then placed under ahydrogen atmosphere (balloon) and stirred for 15 minutes, filteredthrough celite, concentrated under reduced pressure, diluted with DCM (5mL), treated with triethylamine (0.29 mL, 2.07 mmol) and acetyl chloride(0.15 mL, 2.07 mmol), stirred for 30 minutes, quenched with 1M sodiumcarbonate, extracted with ethyl acetate (2×5 mL), dried over sodiumsulfate, concentrated in vacuo to afford tert-butyl3-[(3R)-1-[(2R)-2-acetamidopropyl]-3-piperidyl]azetidine-1-carboxylate(220 mg, 0.648 mmol). tert-butyl3-[(3R)-1-[(2R)-2-acetamidopropyl]-3-piperidyl]azetidine-1-carboxylatewas then condensed with Precursor V using general procedures C and D toafford the title compound. ¹H NMR (400 MHz, Methanol-d₄; HCl Salt) δ7.93 (s, 1H), 7.49 (d, J=2.1 Hz, 1H), 7.35 (d, J=8.5 Hz, 1H), 7.31 (dd,J=8.5, 2.0 Hz, 1H), 6.44 (q, J=7.2 Hz, 1H), 4.39-4.24 (m, 3H), 4.08-3.93(m, 2H), 3.58-3.47 (m, 1H), 3.44-3.34 (m, 1H), 3.17-2.94 (m, 2H),2.86-2.49 (m, 2H), 2.19-2.00 (m, 1H), 2.00 (s, 3H), 1.98-1.94 (m, 3H),1.91 (d, J=7.1 Hz, 3H), 1.83-1.68 (m, 1H), 1.24 (d, J=6.8 Hz, 3H),1.20-1.17 (m, 1H). LCMS [M+H] 598.1.

Example 106

N—((S)-1-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propan-2-yl)acetamide.Precursor VI (270 mg, 1.13 mmol) was condensed with(25)-2-(benzyloxycarbonylamino)propanoic acid (376.7 mg, 1.69 mmol) inDIVIF (3 mL) using2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (642 mg, 1.69 mmol) and N,N-Diisopropylethylamine(0.587 mL, 3.38 mmol) for 12 hours and then poured into ethyl acetate(50 mL), washed with brine (50mL), dried over sodium sulfate, filteredand concentrated under reduced pressure, the residue was purified byflash chromatography using silica gel and a gradient of ethyl acetate(10 to 100%) in hexanes to afford tert-butyl3-[(3R)-1-[(2S)-2-(benzyloxycarbonylamino)propanoyl]-3-piperidyl]azetidine-1-carboxylate(501 mg, 1.13 mmol). tert-butyl3-[(3R)-1-[(2S)-2-(benzyloxycarbonylamino)propanoyl]-3-piperidyl]azetidine-1-carboxylate(501 mg, 1.13 mmol) was dissolved in tetrahydrofuran (6 mL) and treatedwith borane-tetrahydrofuran complex (3.37 mL, 3.37 mmol, 1M intetrahydrofuran) and stirred for 12 hours, quenched with methanol andconcentrated under reduced pressure, the residue was purified by flashchromatography using silica gel and a gradient of methanol (0 to 20%) inDCM to afford tert-butyl3-[(3R)-1-[(2S)-2-(benzyloxycarbonylamino)propyl]-3-piperidyl]azetidine-1-carboxylate(485 mg, 1.13 mmol). tert-butyl3-[(3R)-1-[(2S)-2-(benzyloxycarbonylamino)propyl]-3-piperidyl]azetidine-1-carboxylate(485 mg, 1.13 mmol) was dissolved in methanol (5mL) and palladium oncarbon 10 wt.% (89.4 mg) was added, the mixture was then placed under ahydrogen atmosphere (balloon) and stirred for 15 minutes, filteredthrough celite, concentrated under reduced pressure, diluted with DCM (5mL), treated with triethylamine (0.468 mL, 3.38 mmol) and acetylchloride (0.245 mL, 3.38 mmol), stirred for 30 minutes, quenched with 1Msodium carbonate, extracted with ethyl acetate (2×5 mL), dried oversodium sulfate, concentrated in vacuo to afford tert-butyl3-[(3R)-1-[(2S)-2-acetamidopropyl]-3-piperidyl]azetidine-1-carboxylate(230 mg, 0.678 mmol). tert-butyl3-[(3R)-1-[(2S)-2-acetamidopropyl]-3-piperidyl]azetidine-1-carboxylatewas then condensed with Precursor V using general procedures C and D toafford the title compound.¹H NMR (400 MHz, Methanol-d₄; HCl Salt) δ 7.95(s, 1H), 7.48 (d, J=2.1 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H), 7.31 (dd,J=8.5, 2.1 Hz, 1H), 6.45 (q, J=7.0 Hz, 1H), 4.50-4.39 (m, 1H), 4.37-4.26(m, 2H), 4.18-3.97 (m, 4H), 3.52-3.42 (m, 1H), 3.23-3.06 (m, 2H),3.06-2.90 (m, 1H), 2.76-2.62 (m, 1H), 2.61-2.48 (m, 1H), 2.06-2.00 (m,1H), 2.00 (s, 3H), 2.00-1.93 (m, 1H), 1.91 (d, J=7.1 Hz, 3H), 1.89-1.82(m, 1H), 1.25 (d, J=6.8 Hz, 3H), 1.23-1.14 (m, 1H). LCMS [M+H] 598.2.

Example 107

3-((R)-3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propane-1-sulfonamide.A mixture of the title compound and its diastereomer was prepared usinggeneral procedure B (b) and 3-chloropropane-1-sulfonamide, followed bygeneral procedure C and D with precursor IV. The title compound wasseparated from its diastereomer by SFC using a AD-H column and elutingwith 30% isopropanol (0.1% diethylamine) in CO₂ to give the titlecompound as the first eluting isomer. ¹H NMR (400 MHz, CDCl₃, HCl Salt)δ 7.83 (s, 1H), 7.38 (d, J=2.1 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H), 7.20(dd, J=8.5, 2.1 Hz, 1H), 6.46 (q, J=7.0 Hz, 1H), 4.29-4.17 (m, 2H),4.02-3.96 (m, 1H), 3.95-3.87 (m, 1H), 3.26-3.15 (m, 2H), 3.04-2.85 (m,2H), 2.65-2.49 (m, 3H), 2.23-1.94 (m, 3H), 1.90 (d, J=7.1 Hz, 3H),1.84-1.50 (m, 5H), 1.02-0.88 (m, 1H). LCMS [M+H] 577.1.

Example 108

3-((S)-3-(1-(3-cyano-1-(R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propane-1-sulfonamide.A mixture of the title compound and its diastereomer was prepared asdescribed in the previous example. The title compound was separated fromits diastereomer by SFC using a AD-H column and eluting with 30%isopropanol (0.1% diethylamine) in CO₂ to give the title compound as thesecond eluting isomer. ¹H NMR (400 MHz, CDCl₃, HCl Salt) δ 7.83 (s, 1H),7.38 (d, J=2.1 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 7.20 (dd, J=8.5, 2.1 Hz,1H), 6.45 (q, J=7.0 Hz, 1H), 4.29-4.17 (m, 2H), 4.04-3.89 (m, 2H),3.26-3.16 (m, 2H), 3.00-2.85 (m, 2H), 2.68-2.48 (m, 3H), 2.25-1.92 (m,4H), 1.90 (d, J=7.1 Hz, 3H), 1.85-1.67 (m, 3H), 1.64-1.49 (m, 1H),1.03-0.89 (m, 1H). LCMS [M+H] 577.0.

Example 109

N-(2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)propane-2-sulfonamide.A mixture of the title compound and its diastereomer was prepared usinggeneral procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followedby removal of phthaloyl group with hydrazine hydrate (4 equiv.) inmethanol (0.4M) at ambient temperature for 18 hours. The reactionmixture was diluted with water, extracted with DCM, organic layer wasdried over sodium sulfate, filtered and concentrated in vacuum. Thecrude material was dissolved in DCM and 3 equviv. of triethylamine wasadded to the reaction mixture followed by 1.2 equviv. of2-propanesulfonyl chloride. The reaction mixture was stirred at ambienttemperature until complete conversion (by LCMS) was achieved. Thereaction was quenched with 1M sodium carbonate, extracted withethylacetate, organic phase was dried over sodium sulfate, filtered, andconcentrated in vacuum. The crude product was then used in generalprocedure C and coupled with precursor V using general procedure D. Thetitle compound was separated from its diastereomer by SFC using an AD-Hcolumn and eluting with 20% isopropanol (0.1% diethylamine) in CO₂ togive the free base of as the first eluting isomer. ¹H NMR (400 MHz,Methanol-d₄, HCl Salt) δ 7.93 (s, 1H), 7.50-7.46 (m, 1H), 7.36 (d, J=8.5Hz, 1H), 7.31 (dd, J=8.5, 2.1 Hz, 1H), 6.45 (q, J=7.1 Hz, 1H), 4.40-4.25(m, 2H), 4.14-3.93 (m, 2H), 3.81-3.70 (m, 1H), 3.69-3.61 (m, 1H),3.61-3.43 (m, 2H), 3.39-3.32 (m, 1H), 3.30-3.22 (m, 1H), 3.06-2.88 (m,1H), 2.78-2.57 (m, 2H), 2.23-2.11 (m, 1H), 2.10-1.93 (m, 4H), 1.91 (d,J=7.0 Hz, 3H), 1.38 (d, J=6.8 Hz, 3H), 1.36 (d, J=6.8 Hz, 3H), 1.28-1.17(m, 1H). LCMS [M+H] 648.1.

Example 110

N-(2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)propane-2-sulfonamide.A mixture of the title compound and its diastereomer was prepared usinggeneral procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followedby removal of phthaloyl group with hydrazine hydrate (4 equiv.) inmethanol (0.4M) at ambient temperature for 18 hours. The reactionmixture was diluted with water, extracted with DCM, organic layer wasdried over sodium sulfate, filtered and concentrated in vacuum. Thecrude material was dissolved in DCM and 3 equviv. of triethylamine wasadded to the reaction mixture followed by 1.2 equviv. of2-propanesulfonyl chloride. The reaction mixture was stirred at ambienttemperature until complete conversion (by LCMS) was achived. Thereaction was quenched with 1M sodium carbonate, extracted withethylacetate, organic phase was dried over sodium sulfate, filtered, andconcentrated in vacuum. The crude product was then used in generalprocedure C and coupled with precursor V using general procedure D. Thetitle compound was separated from its diastereomer by SFC using an AD-Hcolumn and eluting with 20% isopropanol (0.1% diethylamine) in CO₂ togive the free base of as the second eluting isomer. ¹H NMR (400 MHz,Methanol-d₄, HCl Salt) ¹H NMR (400 MHz, Methanol-d₄) δ 7.93 (s, 1H),7.48 (d, J=2.1 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H), 7.31 (dd, J=8.5, 2.1 Hz,1H), 6.44 (q, J=7.1 Hz, 1H), 4.38-4.25 (m, 2H), 4.11-3.97 (m, 2H),3.80-3.71 (m, 1H), 3.69-3.60 (m, 1H), 3.61-3.45 (m, 2H), 3.40-3.33 (m,1H), 3.29-3.21 (m, 1H), 3.03-2.93 (m, 1H), 2.77-2.63 (m, 2H), 2.23-2.10(m, 1H), 2.09-1.92 (m, 3H), 1.91 (d, J=7.1 Hz, 3H), 1.89-1.81 (m, 1H),1.38 (d, J=6.8 Hz, 3H), 1.37 (d, J=6.8 Hz, 3H), 1.28-1.14 (m, 1H). LCMS[M+H] 648.1.

Example 111

6-(3-((S)-14(1H-imidazol-5-yl)methyl)piperidin-3-yl)azetidin-1-yl)-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.A mixture of the title compound and its diastereomer was prepared usinggeneral procedure A from 1H-imidazole-5-carbaldehyde using 2:11,2-dichloroethane/DMF as the solvent, followed by procedure C. Theresulting product was condensed with Precursor IV using procedure D. Thetitle compound was separated from its diastereomer by SFC using an AD-H20×250 mm column and eluting with 30% isopropanol (0.1% diethylamine) inCO₂ to give the free base of the title compound as the first elutingisomer and converted to the HCl salt by dissolution in EtOH, cooling to0° C., and addition of 1 equiv. of 0.01M HCl in EtOH. ¹H NMR (400 MHz,Methanol-d₄, HCl Salt) δ 7.94 (s, 1H), 7.64 (d, J=1.1 Hz, 1H), 7.48 (d,J=2.1 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.31 (dd, J=8.5, 2.1 Hz, 1H),7.01 (s, 1H), 6.45 (q, J=7.0 Hz, 1H), 4.33-4.18 (m, 2H), 4.03-3.93 (m,1H), 3.93-3.84 (m, 1H), 3.58 (s, 2H), 3.34-3.32 (m, 1H), 2.98-2.85 (m,2H), 2.68-2.54 (m, 1H), 2.12-2.01 (m, 1H), 1.90 (d, J=7.0 Hz, 3H),1.87-1.70 (m, 4H), 0.98-0.84 (m, 1H). LCMS [M+H] 536.0.

Example 112

6-(3-((R)-1-((1H-imidazol-5-yl)methyl)piperidin-3-yl)azetidin-1-yl)-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.A mixture of the title compound and its diastereomer was prepared usinggeneral procedure A from 1H-imidazole-5-carbaldehyde using 2:11,2-dichloroethane/DMF as the solvent, followed by procedure C. Theresulting product was condensed with Precursor IV using procedure D. Thetitle compound was separated from its diastereomer by SFC using an AD-H20×250 mm column and eluting with 30% isopropanol (0.1% diethylamine) inCO₂ to give the free base of the title compound as the second elutingisomer and converted to the HCl salt by dissolution in EtOH, cooling to0° C., and addition of 1 equiv. of 0.01M HCl in EtOH. ¹H NMR (400 MHz,Methanol-d₄, HCl Salt) δ 7.94 (s, 1H), 7.64 (d, J=1.2 Hz, 1H), 7.49 (d,J=2.1 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.31 (dd, J=8.5, 2.1 Hz, 1H),7.01 (s, 1H), 6.45 (q, J=7.0 Hz, 1H), 4.34-4.16 (m, 2H), 4.03-3.86 (m,2H), 3.58 (s, 2H), 3.34-3.32 (m, 1H), 2.97-2.84 (m, 2H), 2.67-2.56 (m,1H), 2.13-2.01 (m, 1H), 1.90 (d, J=7.0 Hz, 3H), 1.88-1.70 (m, 3H),1.72-1.53 (m, 1H), 0.97-0.83 (m, 1H). LCMS [M+H] 536.0.

Example 113

1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-6-(3-((S)-1-(3-(methylsulfonyl)propyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine.A mixture of the title compound and its diastereomer was prepared usingprocedure B(b) using 1-bromo-3-(methylsulfonyl)propane, followed bygeneral procedure C and coupling with precursor II using generalprocedure D. The title compound was separated from its diastereomer bySFC using an IC 20×250 mm column and eluting with 40% ethanol (0.1%diethylamine) in CO₂ to give the free base of the title compound as thefirst eluting isomer. ¹H NMR (400 MHz, Methanol-d₄, HCl Salt) δ 7.74 (s,1H), 7.45 (d, J=2.1 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H), 7.26 (dd, J=8.5,2.1 Hz, 1H), 6.29 (q, J=7.0 Hz, 1H), 4.32-4.22 (m, 2H), 4.01-3.94 (m,2H), 3.51-3.45 (m, 1H), 3.35 (s, 2H), 3.34-3.32 (m, 1H), 3.28-3.23 (m,3H), 3.17-3.10 (m, 1H), 3.03 (s, 3H), 2.75-2.63 (m, 1H), 2.50 (s, 3H),2.28-2.20 (m, 2H), 2.10-1.91 (m, 3H), 1.87 (d, J=7.1 Hz, 3H), 1.82-1.70(m, 1H), 1.23-1.14 (m, 1H). LCMS [M+H] 565.0.

Example 114

1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-6-(3-((R)-1-(3-(methylsulfonyl)propyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine.A mixture of the title compound and its diastereomer was prepared usingprocedure B(b) using 1-bromo-3-(methylsulfonyl)propane, followed bygeneral procedure C and coupling with precursor II using generalprocedure D. The title compound was separated from its diastereomer bySFC using an IC 20×250 mm column and eluting with 40% ethanol (0.1%diethylamine) in CO₂ to give the free base of the title compound as thesecond eluting isomer. ¹H NMR (400 MHz, Methanol-d₄, HCl Salt) δ 7.74(s, 1H), 7.45 (d, J=2.1 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H), 7.26 (dd,J=8.5, 2.1 Hz, 1H), 6.29 (q, J=7.0 Hz, 1H), 4.32-4.22 (m, 2H), 4.02-3.94(m, 2H), 3.51-3.38 (m, 1H), 3.35 (s, 2H), 3.26 (t, J=7.3 Hz, 2H),3.21-3.11 (m, 2H), 3.03 (s, 3H), 2.84-2.73 (m, 1H), 2.73-2.59 (m, 1H),2.50 (s, 3H), 2.31-2.20 (m, 2H), 2.13-1.91 (m, 3H), 1.87 (d, J=7.1 Hz,3H), 1.84-1.69 (m, 1H), 1.25-1.11 (m, 1H). LCMS [M+H] 565.0.

Example 115

1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((S)-1-(3-(methylsulfonyl)propyl)piperidin-3-yl)azetidin-1-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine.A mixture of the title compound and its diastereomer was prepared usingprocedure B(b) using 1-bromo-3-(methylsulfonyl)propane, followed bygeneral procedure C and coupling with precursor V using generalprocedure D. The title compound was separated from its diastereomer bySFC using an IC 20×250 mm column and eluting with 35% ethanol (0.1%diethylamine) in CO₂ to give the free base of the title compound as thefirst eluting isomer. ¹H NMR (400 MHz, Methanol-d₄, HCl Salt) δ 7.93 (s,1H), 7.49 (d, J=2.0 Hz, 1H), 7.35 (d, J=8.5 Hz, 1H), 7.30 (dd, J=8.5,2.0 Hz, 1H), 6.44 (q, J=7.1 Hz, 1H), 4.35-4.28 (m, 2H), 4.06-3.97 (m,2H), 3.50-3.47 (m, 1H), 3.42-3.34 (m, 3H), 3.28-3.20 (m, 2H), 3.15-3.10(m, 1H), 3.03 (s, 3H), 2.76-2.64 (m, 2H), 2.30-2.16 (m, 2H), 2.10-1.93(m, 3H), 1.91 (d, J=7.1 Hz, 3H), 1.82-1.67 (m, 1H), 1.25-1.12 (m, 1H).LCMS [M+H] 619.1.

Example 116

1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-(3-(methylsulfonyl)propyl)piperidin-3-yl)azetidin-1-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine.A mixture of the title compound and its diastereomer was prepared usingprocedure B(b) using 1-bromo-3-(methylsulfonyl)propane, followed bygeneral procedure C and coupling with precursor V using generalprocedure D. The title compound was separated from its diastereomer bySFC using an IC 20×250 mm column and eluting with 35% ethanol (0.1%diethylamine) in CO₂ to give the free base of the title compound as thesecond eluting isomer. ¹H NMR (400 MHz, Methanol-d₄, HCl Salt) δ 7.93(s, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.35 (d, J=8.5 Hz, 1H), 7.31 (dd,J=8.5, 2.0 Hz, 1H), 6.44 (q, J=7.1 Hz, 1H), 4.37-4.26 (m, 2H), 4.08-3.96(m, 2H), 3.54-3.44 (m, 1H), 3.26 (t, J=7.4 Hz, 2H), 3.22-3.15 (m, 3H),3.14-3.12 (m, 1H), 3.03 (s, 3H), 2.75-2.64 (m, 2H), 2.31-2.20 (m, 2H),2.13-1.91 (m, 3H), 1.91 (d, J=7.1 Hz, 3H), 1.82-1.69 (m, 1H), 1.25-1.12(m, 1H). LCMS [M+H] 619.1.

Biological Samples and Assays

The following general materials and methods were used, where indicated,or may be used in the Examples. Standard methods in molecular biologyare described in the scientific literature (see, e.g., Sambrook andRussell (2001) Molecular Cloning, 3^(rd) ed., Cold Spring HarborLaboratory Press, Cold Spring Harbor, N.Y.; and Ausubel, et al. (2001)Current Protocols in Molecular Biology, Vols. 1-4, John Wiley and Sons,Inc. New York, N.Y., which describes cloning in bacterial cells and DNAmutagenesis (Vol. 1), cloning in mammalian cells and yeast (Vol. 2),glycoconjugates and protein expression (Vol. 3), and bioinformatics(Vol. 4)).

The scientific literature describes methods for protein purification,including immunoprecipitation, chromatography, electrophoresis,centrifugation, and crystallization, as well as chemical analysis,chemical modification, post-translational modification, production offusion proteins, and glycosylation of proteins (see, e.g., Coligan, etal. (2000) Current Protocols in Protein Science, Vols. 1-2, John Wileyand Sons, Inc., NY).

Software packages and databases for determining, e.g., antigenicfragments, leader sequences, protein folding, functional domains,glycosylation sites, and sequence alignments, are available (see, e.g.,GCG Wisconsin Package (Accelrys, Inc., San Diego, Calif.); and DeCypher™(TimeLogic Corp., Crystal Bay, Nev.).

Multiple assays that can be used to evaluate the compounds of thepresent invention are known to the skilled artisan and/or are describedin the patent and scientific literature (see, e.g., US 2006/0004010; US2002/0173524; Imai et al. (1997) J. Biol. Chem. 272:15036-15042; Imai etal.

(1998) J. Biol. Chem. 273:1764-1768, each of which is herebyincorporated by reference). The following procedures are representativeof the types of experiments that can be used to demonstrate, forexample, the CCR4 compounds' antagonistic activity, inhibitory activityfor effector cell functions, TNFα-regulating activity, and efficacy inanimal disease models.

Calcium Flux Assay. Compounds were evaluated in a calcium flux assaysubstantially performed as follows. Chem5-hCCR4 cells (EMD Millipore,Hayward, Calif.; HTS009C) were cultured under standard conditions andfrozen in aliquots of 10×10⁶ cells/mL. The day prior to compoundtesting, a vial was rapidly thawed and pipetted into 20 mL media(DMEM+10% FBS+1% Pen-Strep+1% L- glutamine). Cells were harvested bycentrifugation and re-suspended in fresh culture medium. 25 μL of cellsuspension was seeded into 384-well plates (Corning, Tewksbury, Mass.;CellBind with black wall/clear bottom). The plates were centrifuged at300 g for 10 seconds and incubated overnight at 37° C. and 5% CO₂. Theday of compound testing, media was removed from the plates and 25 μLserum free media was added to each well. Plates were returned to theincubator for 2 h. 25 μL assay buffer (Hank's balanced salt solution+20mM HEPES pH 7.4) containing FLIPR Calcium 6 dye (Molecular Devices,Sunnyvale, Calif.; #R8191) and probenecid (2.5 mM) was added to eachwell and incubated at 37° C. and 5% CO₂for 2 h. Compounds in DMSO wereadded to the plates using an HP D300e digital dispenser, and all wellswere normalized to contain 0.25 μL (0.5%) DMSO. Plates were incubatedfor 1 hour at 37° C. and 5% CO₂. CCL22 (Peprotech; Rockyhill, N.J.) wasdiluted in assay buffer containing 0.1% BSA to 7.5 nM (corresponding to5×EC₈₀ of 1.5 nM).

Assay plates and working solution of CCL22 were transferred to theFlexStation plate reader (Molecular Devices) at 37° C. for 5 min ofequilibration. Fluorescence recordings at 485 excitation/525 emissionwere performed at 2.5 second intervals. At t=16 seconds, 12.5 μL ofCCL22 solution was added to each well and reads continued for 30 secondsat 2.5 second intervals. The minimum fluorescence (F_(min)) wascalculated by averaging the reads prior to ligand addition and thechange in fluorescence (ΔF) was calculated by subtracting the F_(min)from the average of the reads following ligand addition. The responseΔF/F_(min) was plotted as a function of the compound concentration andthe IC50 values were determined by non-linear regression analysis usinga 4-parameter fit in either PRISM software (GraphPad; La Jolla, Calif.)or Dotmatics Browser.

Using the calcium flex assay described herein, the activity for severalcompounds described herein was determined.

The potency levels are set forth in Table 2, wherein IC₅₀: A<0.1 μM;B=0.1-0.5 μM; and C>0.5 μM.

TABLE 2 Example Number Potency 1 C 2 C 3 C 4 B 5 C 6 A 7 B 8 A 9 C 10 A11 B 12 B 13 A 14 A 15 B 16 C 17 A 18 A 19 A 20 B 21 A 22 C 23 A 24 A 25A 26 A 27 A 28 A 29 A 30 A 31 A 32 B 33 A 34 A 35 A 36 A 37 A 38 A 39 C40 A 41 A 42 B 43 A 44 B 45 B 46 B 47 A 48 A 49 A 50 A 51 B 52 A 53 B 54A 55 A 56 A 57 A 58 B 59 A 60 A 61 A 62 A 63 A 64 A 65 A 66 A 67 A 68 B69 A 70 A 71 A 72 B 73 A 74 B 75 A 76 B 77 A 78 A 79 B 80 A 81 B 82 A 83B 84 A 85 A 86 B 87 A 88 B 89 A 90 A 91 A 92 A 93 A 94 B 95 A 96 B 97 A98 B 99 A 100 A 101 A 102 B 103 A 104 A 105 A 106 A 107 A 108 B 109 A110 B 111 B 112 A 113 B 114 A 115 B 116 A

Potent and Selective C-C Motif Chemokine Receptor (CCR4) AntagonistsPotentiate Anti-Tumor Immune Responses by Inhibiting Regulatory T Cells(Tre_(g))

Naturally occurring suppressive CD4⁺ Foxp3⁺ Tre_(g) are essential forimmune tolerance. Although Tre_(g)-mediated suppression of effectorcells is important to control inflammatory responses and preventautoimmune diseases, the presence of T_(reg) in the tumormicroenvironment (TME) has been shown to dampen anti-tumor immuneresponses. Human T_(reg) express CCR4, the receptor for the chemokinesCCL17 and CCL22. These chemokines are produced by tumor cells ortumor-associated macrophages and dendritic cells, as well as by effectorT cells (T_(eff)). Preclinical and clinical data in various cancer typessupports a role for CCR4-mediated recruitment and accumulation ofT_(reg) in the TME which can be associated with poor prognosis. Further,recent longitudinal studies in patients receiving IO agents demonstratean influx of Tre_(g) in responding patients which may dampen optimalanti-tumor responses. Therefore, CCR4 is an ideal target to selectivelyblock T_(reg) recruitment into the TME.

Multiple structurally unique series of selective small moleculeantagonists of CCR4 have been developed. These antagonists have cellularpotencies in multiple assays (including in a functional chemotaxis assaywith primary human T_(reg) in 100% serum) in the low double-digit nMrange. Representative compounds are selective against other chemokinereceptors, GPCRs and ion channels, including the hERG channel, and lackinhibition of common human CYP450 enzymes. Moreover, compounds haveexcellent in vitro and in vivo ADME properties, consistent withconvenient oral dosing. In preclinical syngeneic tumor models, our CCR4antagonists block T_(reg) migration and support expansion of activatedT_(eff). In contrast to the non-selective approach of depletinganti-CCR4 antibodies, our compounds reduce T_(reg) in the tumor, but notin peripheral tissues such as blood, spleen or skin. In preclinicalefficacy studies, CCR4 antagonists potentiate the anti-tumor effects ofvarious checkpoint inhibitors and immune stimulators such as anti-PD-L1and anti-CD137 antibodies. Enhanced tumor growth inhibition andincreases in the percentage of tumor free mice when these agents arecombined with CCR4 antagonists, without any gross toxicity, wasobserved.

Chemotaxis Assays. Generally speaking, chemotaxis assays may beperformed using 5 μm filterplates (Neuroprobe) with the chemoattractant(MDC, TARC, or SDF) placed in the lower chamber, and a cell suspensionof 100,000 CEM cells in the upper chamber. The assays may be incubated1-2 h at 37° C., and the number of cells in the lower chamber quantifiedby the CyQUANT assay (Molecular Probes).

The following serum chemotaxis assay was used to determine the extent towhich the compounds of the present invention block cellular migrationmediated through CCR4. The assay was performed using the ChemoTX(Gaithersburg, MD) migration system with a 5μm pore size polycarbonatetrach-etch (PCTE) membrane. CCRF-CEM cells which express CCR4 werecollected by centrifugation at 400×g at room temperature, then suspendedat 2 million cells/mL in human serum. Compounds (or an equivalent volumeof solvent (DMSO)) were then added to the cell/serum mixture at a finalDMSO concentration of 0.25% (v/v), followed by a 30-minute compoundpre-incubation period. Separately, recombinant human MDC was diluted to0.9 nM in 1× HBSS with 0.1% BSA, and 29 μL of diluted MDC was placed inthe lower wells of the ChemoTX plate. The polycarbonate (or PCTE)membrane (5 μm pore size) was placed onto the plate, and 50 of thecell/compound mixture was transferred into each well of the membrane.The plates were incubated at 37° C. for 60 minutes, after which thepolycarbonate membranes were removed, and 10 of the DNA-intercalatingagent CyQUANT was added to the lower wells. The amount of fluorescence,corresponding to the number of migrated cells, was measured using anEnvision plate reader (PerkinElmer; Waltham, Mass.)

Detection of radiolabeled TARC and/or MDC binding to CCR4 Protocol A.Source plates of chemical libraries may be obtained from commercialvendors and may contain individual compounds at 5 mg/mL in DMSO. Fromthese, multiple compound plates containing 10 compounds in each well maybe prepared and then diluted in 20% DMSO to a concentration of 50 μg/mL.An aliquot of 20 μL of each mixture may be put into the test plates andstored frozen until use.

A CCR4 expressing stable transfectant cell line may be prepared usingcurrent standard molecular biological methods. The CCR4 transfectantsmay be cultured in IMDM-5% FBS, and harvested when the concentration isbetween 0.5-1.0×10⁶ cells/mL. The cells may be centrifuged andresuspended in assay buffer (20 mM HEPES, pH 7.1, 140 mM NaCl, 1 mMCaCl₂, 5 mM MgCl₂, and with 0.2% BSA) to a concentration of 5.6×10⁶cells/mL. To establish the screening assays, 0.09 mL of cells may beadded to the assay plates containing the compounds (yielding a finalcompound concentration of 1-5 μg/mL each (˜2-10 μM)), and then 0.09 mLof ¹²⁵I-TARC or ¹²⁵I-MDC diluted in assay buffer (final concentration˜50 μM, with 30,000 cpm per well) may be added. The plates may then besealed and incubated for approximately 3 hrs at 4° C. on a shakerplatform. The assay plates may be harvested using Packard filter plates,pre-soaked in 0.3% PEI (polyethyleneimine) solution, on a Packard vacuumcell harvester. Scintillation fluid (50 μL) was added to all wells andthe plates may be sealed and counted in a Top Count scintillationcounter. Control wells containing either diluent only (for total counts)or excess MDC or TARC (1 μg/mL, for non-specific binding) may be used tocalculate the percent of total inhibition for each set of compounds.IC₅₀ values are those concentrations required to reduce the binding oflabeled MDC or TARC to the receptor by 50%.

Detection of radiolabeled TARC and/or MDC binding to CCR4 Protocol B.¹²⁵I-labelled TARC and MDC are available from commercial sources (e.g.,Perkin Elmer Life Sciences). All buffers and materials are availablefrom commercial sources (e.g., Sigma).

To measure binding of ¹²⁵I-TARC or ¹²⁵I-MDC to cells expressing CCR4(e.g., CEM cells (e.g., ATCC HB-12624)), the ¹²⁵I-TARC or ¹²⁵I-MDC isdiluted to a concentration of approximately 200 pM in a buffered salinesolution (e.g., RPMI supplemented with 0.5% BSA), and added to an equalvolume of a suspension of cells (e.g., CEM cells at 5×10⁶ cells/mL). Theresulting mixture is incubated for a period of time (e.g., 2 hrs), andthe unbound ¹²⁵I-TARC or ¹²⁵I-MDC is separated from the cells byfiltration, e.g., by passage through GF/B filter plate (PackardBiosciences) pre-treated with 0.3% polyethyleneimine (Sigma), using aPackard Filtermate 96 (Packard Biosciences). The amount of ¹²⁵I-TARC or¹²⁵I-MDC retained with the cells on the filterplate is measured byadding a small amount of scintillation fluid (e.g., 50 μL ofMicroscint-20 Packard Biosciences)), and reading scintillation onappropriate detection equipment, e.g., a Packard TopCount 383 (PackardBiosciences).

Non-specific binding of ¹²⁵I-TARC or ¹²⁵I-MDC can be estimated bymeasuring the amount of ¹²⁵I-TARC or ¹²⁵I-MDC retained with the cells onthe filterplate when the assay is performed in the presence of a largeexcess of unlabeled TARC or MDC. Inhibition of ¹²⁵I-TARC or ¹²⁵I-MDCbinding to CCR4 is defined as a decrease in the retention of ¹²⁵I-TARCor ¹²⁵I-MDC to the cells on the filterplate.

Calcium Mobilization Assay. Calcium mobilization experiments may beperformed by labeling the human T-cell line CEM with NDO-1 dye (45 minat room temperature), washing with PBS, and re-suspending into fluxbuffer (HBSS with 1% FBS). For each experiment, 1×10⁶ cells may beincubated at 37° C. in the cuvette of a PTI spectrometer, and the ratioof 410/490 nm emission plotted over time (typically 2-3 minutes), withcompounds added at 5 seconds, followed by MDC, TARC or other chemokines.

Production of TNFα. The present invention contemplates the use of amurine model of TNFα production by LPS stimulation. A CCR4 antagonisticcompound(s) may be suspended in a medium, orally administered to a mouse(male, C57BL/6), and after 0.5 hour LPS (055:B5, Sigma) peritoneallyadministered to the mouse at a dose of 60 mg/kg. To the control groups,only the medium may be administered. Sixty min after LPS treatment,heparin-added blood collection may be conducted from the abdominal venacava under ether anesthesia, and centrifuged (12,000 rpm) at 4° C. for 3min to provide plasma (which may be stored at −80° C. before use). TNFαin the plasma may be quantified using an ELISA kit (R&D systems;Minneapolis, Minn.).

Efficacy of CCR4 Antagonists for Therapeutic Indications. Arepresentative procedure for evaluating the efficacy of CCR4 antagonistsfor treatment of septic shock is described herein. An animal model ofendotoxic shock may be induced by injecting mice with LPS. Three groups(15 mice per group) may be treated with an i.p. injection of an LPS dosethat produces 90% mortality in mice. One group of mice may also receivePBS and Tween 0.5% i.p. 30 min before LPS administration. A second groupof mice may also receive different doses of the CCR4 antagonist(s) giveneither i.p., IV, SC, IM, PO or via any other mode of administration 30min before, or concurrently with, LPS administration. A third group ofmice may serve as a positive control and consist of mice treated witheither mouse IL-10 i.p. or anti-TNF antibodies i.p. 30 min before LPSadministration. Mice are monitored for death for 72 h following the LPSinjection.

Asthma. Representative procedures for evaluating the efficacy of CCR4antagonists for treatment of asthma are as described herein. ProcedureA: An animal model of asthma may be induced by sensitizing mice to anexperimental antigen (e.g. OVA) by standard immunization techniques, andsubsequently introducing that same antigen into the mice's lungs byaerosolization. Three groups of mice (10 mice per group) may be activelysensitized on Day 0 by a single i.p. injection with 100 μg OVA in PBS,along with an IgE-selective adjuvant (e.g. aluminum hydroxide). Elevendays' post-sensitization, at the peak of their IgE response, the micemay be placed in a Plexiglas chamber and challenged with aerosolized OVA(1%) for 30 min using the ultrasonic nebulizer (e.g., De Vilbliss;Ingersoll Rand; Dublin, IE). One group of mice may additionally receivePBS and Tween 0.5% i.p. at the initial sensitization, and at differentdosing schedules thereafter, up until the aerosolized OVA challenge. Asecond group of mice may receive different doses of the CCR4antagonist(s) given either i.p., IV, SC, IM, PO or via any other mode ofadministration at the initial sensitization, and at different dosingschedules thereafter, up until the aerosolized OVA challenge. A thirdgroup of mice, serving as a positive control, may be treated with eithermouse IL-10 i.p., anti-IL-4 antibodies i.p., or anti-IL5 antibodies i.p.at the initial sensitization, and at different dosing schedulesthereafter, up until the aerosolized OVA challenge.

Following the aerosolized OVA challenge, mice may be analyzed atdifferent time points for pulmonary function, cellular infiltrates inbronchoalveolar lavage (BAL), histological examination of lungs, andmeasurement of serum OVA-specific IgE titers.

Procedure B. Ovalbumin (OVA, 0.2 mg/mL) and Alum (8 mg/mL) prepared inphysiological saline may be intraperitoneally administered (500 μL) tomice (male, C57BL/6) on Day 1 (test starting day) and Day 8 (1 weekthereafter), to sensitize the mice. On Days 15 to 21, mice may be placedin an inhalation chamber (W: 240 mm×L: 240 mm×H: 120 mm), and a 2% OVAsolution may be sprayed with an ultrasonic wave-type nebulizer (NE-U12;Omron, San Ramon, Calif.) for 20 min to conduct induction. A CCR4antagonist(s) may be suspended in a medium and administered orally at 30min before OVA sensitization on Day 8 and at 30 min before OVA inductionon Days 15 to 21. For a control group, only the medium may beadministered. Three h post-OVA inhalation on Day 21, the mice may beexsanguinated, catheter tubes inserted into their trachea, and lungswashed with heparin-containing physiological saline (10 U/mL) to providea bronchoalveolar lavage fluid (BALF). Leukocyte number in BALF may becounted using hemocyte counter (SF-3000; Sysmex, Kobe, JP).

Dermatitis. Representative procedures for evaluating the efficacy ofCCR4 antagonists for treatment of dermatitis are as described herein.Mouse DTH Model. Mice (male, Balb/c) may be shaved on the abdomen withhair clippers, and to the abdomen may be applied ethanol solution (100μL) of 7% (w/v) 2,4,6-trinitrochlrobenzene (TNCB), to sensitize themice. Seven days' post-sensitization, a 1% (w/v) TNCB solution in oliveoil (20 μL) may be applied to the auricle of the mice (both sides of theright ear), to conduct induction. A CCR4 antagonist(s) may be dissolvedin a medium, applied to both sides of the right ear (20 μL) 2 h beforeapplying TNCB. To the control groups, only the medium may be applied.Immediately following compound(s) administration and 24 h after TNCBapplication, the thickness of the mice auricles may be measured withDialthickness gauge (Ozaki Seisakusho, JP), which may be used asindicator for efficacy in mouse DTH model.

Dermatitis Model to which Hapten is Applied. To the auricle (both sidesof the right ear) of the mice (male, Balb/c), 1% (w/v) TNCB solution(acetone:olive oil=4:1) (20 μL) may be applied to conduct firstsensitization. Seven days' post-sensitization, 1% (w/v) TNCB(acetone:olive oil=4:1) (20 μL) may be applied to the auricle of themice, to conduct induction (Day 0); this procedure may be repeated onDays 2, 4, 6, 8, 10, 12, 14 and 16. A CCR4 antagonist(s) may bedissolved in a medium, and applied to both sides of the right ear (20μL) two h before applying TNCB. To the control groups, medium only maybe applied. Immediately following compound(s) administration and 24 hpost-TNCB application, the thickness of the mice auricles may bemeasured with Dialthickness gauge, which may be used as an indicator ofefficacy in mouse dermatitis model to which hapten is continuouslyapplied.

Infection. A representative procedure for evaluating the efficacy ofCCR4 antagonists for augmenting protective immunity against viruses,bacteria and parasites is as described herein. Protective immunity tomicrobial pathogens is frequently mediated by Th1 regulatory T cells.Because CCR4 antagonists are believed to be inhibitors of Th2 regulatorycells, they may alter the cross-regulation that normally exists betweenTh1 and Th2 cells and potentiate Thl cells, thereby augmentingprotection against infectious disease.

Three groups of mice (15 mice per group) may be infected with theintracellular parasite Leishmania major (L. major) by injecting L. majorpromastigotes SC into their left hind footpads. Four weeks afterinfection, the mice may be challenged with either Leishmaniafreeze-thawed antigen, or PBS as a negative control, in thecontra-lateral footpad. One group of mice may also receive PBS and Tween0.5% i.p. at the initial sensitization, and at different dosingschedules thereafter, up until the Leishmania antigen challenge. Asecond group of mice may receive different doses of the CCR4antagonist(s) given either i.p., IV, SC, IM, PO or via any other mode ofadministration at the initial sensitization, and at different dosingschedules thereafter, up until the Leishmania antigen challenge. A thirdgroup of mice, serving as positive control, may consist of mice treatedwith either IL-12, anti-IL-4 antibodies i.p., or anti-IL-5 antibodiesi.p. at the initial sensitization, and at different dosing schedulesthereafter, up until the Leishmania antigen challenge.

Over the next 48 h, footpad swelling, caused by a Delayed-TypeHypersensitivity reaction to the Leishmania antigen challenge, may bemonitored with a metric caliper. The response of draining lymph node Tcells to Leishmania antigen stimulation in vitro may also be measured,both at the level of proliferation, cytokine production, and otherphenotypic criteria.

Rheumatoid Arthritis. Rheumatoid Arthritis (RA), which is generallycharacterized by chronic inflammation in the membrane lining (thesynovium) of the joints, affects approximately 1% of the U.S.population, or 2.1 million people in the U.S. Further understanding ofthe role of cytokines, including TNF-α and IL-1, in the inflammatoryprocess has enabled the development and introduction of a new class ofdisease-modifying antirheumatic drugs (DMARDs). Agents (some of whichoverlap with treatment modalities for RA) include ENBREL (etanercept),REMICADE (infliximab), HUMIRA (adalimumab) and KINERET (anakinra).Though some of these agents relieve symptoms, inhibit progression ofstructural damage, and improve physical function in particular patientpopulations, there is still a need for alternative agents with improvedefficacy, complementary mechanisms of action, and fewer/less severeadverse effects.

A representative procedure for evaluating the efficacy of CCR4antagonists for treatment of rheumatoid arthritis is as describedherein. An animal model of rheumatoid arthritis may be induced inrodents by injecting them with type II collagen in selected adjuvants.Three rodent groups, each consisting of 15 genetically-susceptible miceor rats, may be injected SC or intra-dermally with type II collagenemulsified in Complete Freund's Adjuvant at days 0 and 21. One group ofrodents may additionally receive PBS and Tween 0.5% i.p. at the initialsensitization, and at different dosing schedules thereafter. A secondgroup of rodents may receive different doses of the CCR4 antagonist(s)given either i.p., IV, SC, IM, PO or via any other mode ofadministration at the initial sensitization, and at different dosingschedules thereafter. A third group, serving as positive control, mayconsist of rodents treated with either mouse IL-10 i.p., or anti-TNFantibodies i.p. at the initial sensitization, and at different dosingschedules thereafter.

Animals may be monitored from weeks 3 until 8 for the development ofswollen joints or paws, and graded on a standard disease-severity scale.Disease severity may be confirmed by histological analysis of j oints.

Systemic Lupus Erythematosus. A representative procedure for evaluatingthe efficacy of CCR4 antagonists for treatment of Systemic LupusErythematosus (SLE) is as described herein. Female NZB/W Fl micespontaneously develop an SLE-like pathology commencing at 6 months ofage that is characterized by proteinuria, serum autoantibodies,glomerulonephritis, and eventually death.

Three groups of NZB/W mice, each comprising 20 mice per group, may beevaluated. One group of mice may receive PBS and Tween 0.5% i.p. soonafter weaning, and thereafter at varying dosing schedules. A secondgroup of mice may receive different doses of the CCR4 antagonist(s)given either i.p., IV, SC, IM, PO or via any other mode ofadministration soon after weaning, and thereafter at varying dosingschedules. A third group of mice, serving as positive control, maycomprise mice treated with anti-IL-10 antibodies given soon afterweaning, and thereafter at varying dosing schedules. Disease developmentmay be monitored in terms of eventual mortality, kidney histology, serumautoantibody levels, and proteinuria.

Cancer-related Malignancy. A representative procedure for evaluating theefficacy of CCR4 antagonists for treatment of cancer is as describedherein. Mice homozygous for the severe combined immune deficiencyspontaneous mutation Prkdc^(scid)(SCID mice), are characterized by anabsence of functional T cells and B cells, lymphopenia,hypogammaglobulinemia, and a normal hematopoietic microenvironment.Additional mouse genetic backgrounds can result in lack of naturalkiller cells (in NOD-SCID); while the addition of mutations in IL2receptor gamma chain results in loss of much cytokine signalingresulting in highly immune-deficient mice (NSG). Immuno-deficient mice(SCID mice, NOD-SCID mice, NSG or other) can be engrafted with a humanimmune system following transplant of PBMCs, CD34+ hematopoietic stemcells, or isolated immune effector populations. These humanized mice maybe transplanted cultured established human tumor cell lines (xenograft)or with primary human tumor cells to create a patient derived xenograft(PDX). Additionally, normal mouse strains may be transplanted with avariety of well-characterized mouse tumor lines, including the thymomaEL4 cell line, which have been transfected with OVA to allow easyevaluation of tumor-specific antigen responses following vaccinationwith OVA. Three groups of mice from any of these tumor models may betested for CCR4 antagonist efficacy. One group receives PBS and Tween0.5% i.p. soon after tumor transplant, and thereafter at varying dosingschedules. A second group receives different doses of the CCR4antagonist(s) given either i.p., IV, SC, IM, PO or via any other mode ofadministration following tumor transplant, and thereafter at varyingdosing schedules. A third group, serving as positive control, maycomprise mice treated with either anti-IL-4 antibodies, anti-IFNyantibodies, IL-4, or TNF, given i.p. soon after tumor transplant, andthereafter at varying dosing schedules. A second group receivesdifferent doses of the CCR4 antagonist(s) given either i.p., IV, SC, IM,PO or via any other mode of administration following tumor transplant,and thereafter at varying dosing schedules. A third group, serving aspositive control, may comprise mice treated with either anti-IL-4antibodies, anti-IFNy antibodies, IL-4, or TNF, given i.p. soon aftertumor transplant, and thereafter at varying dosing schedules.

Efficacy may be monitored via tumor growth versus regression. In thecase of the OVA-transfected EL4 thymoma model, cytolytic OVA-specificresponses may be measured by stimulating draining lymph node cells withOVA in vitro, and measuring antigen-specific cytotoxicity at varioustimes, such as 72 h.

Allograft Transplantation Models. Allograft mouse tumor systems, alsoknown as syngeneic models, may be used to evaluate the compounds of thepresent invention. In contrast to conventional xenograft models, whichoften lack relevance due to the animals' immunocompromised status, thehost immune system is normal in syngeneic models, which may more closelyrepresent the native tumor micro-environment. Because they retain intactimmune systems, syngeneic mouse models are particularly relevant forstudies of immunologically-based targeted therapies, that modulate theimmune system's ability to seek out and destroy cancer cells. Forexample, the MC38 model of colorectal cancer can be used to explore theactivity of treatment with a CCR4 inhibitor. Treatment with the CCR4inhibitor and/or other agents may be initiated prior to, along with, orafter MC38 cancer cells have been implanted or injected into recipientmice. Mice are then divided or randomized into treatment groups, eachcontaining multiple mice, and the impact of treatment can be measured.Endpoints for anti-tumor responses include the absence or presence of atumor, it's size, time to a size (including any detection at all) ortime to regression, long term regression, or other accepted endpoints.Additional endpoints of activity include, for example, acharacterization of the immune cell populations in and around the tumoror systemically or markers of immune cell responses (e.g. cytokinelevels).

Syngeneic models consist of tumor tissues derived from the same geneticbackground as a given mouse strain. Cancerous cells or solid tumors maybe transplanted into a host mouse. Because the cancer tissues and therecipient share ancestry, the transplant is not rejected by the host'simmune system. Tissues may then be monitored for changes such as growthor shrinkage, metastasis, and survival rate. Therapeutic interventionsmay be performed and the results assessed to understand the treatmentpotentials.

A discussion of syngeneic models and other tumor models for efficacydeterminations is set forth in Teicher, B A, (October 2006) Mol CancerTher 5:2435. Multiple syngeneic tumor models with well-characterizedresponses to known immune checkpoint inhibitors (e.g., anti-PDL-1,anti-PD-1 and anti-CTLA-4) are commercially available (e.g., GenScript(Piscataway, N.H.) and Charles River Labs (Wilmington, Mass.)).

Psoriasis. Psoriasis, a constellation of common immune-mediated chronicskin diseases, affects more than 4.5 million people in the U.S., ofwhich 1.5 million are considered to have a moderate-to severe form ofthe disease. Moreover, over 10% of patients with psoriasis developpsoriatic arthritis, which damages the bone and connective tissue aroundthe joints. An improved understanding of the underlying physiology ofpsoriasis has resulted in the introduction of agents that, for example,target the activity of T lymphocytes and cytokines responsible for theinflammatory nature of the disease. Such agents include theTNF-ainhibitors (also used in the treatment of rheumatoid arthritis(RA)), including ENBREL (etanercept), REMICADE (infliximab) and HUMIRA(adalimumab)), and T-cell inhibitors such as AMEVIVE (alefacept) andRAPTIVA (efalizumab). Though several of these agents are effective tosome extent in certain patient populations, none have been shown toeffectively treat all patients.

A representative procedure for evaluating the efficacy of CCR4antagonists for treatment of psoriasis is as described herein. A rodentmodel of psoriasis may be generated by intravenously transferring apopulation of purified T cells (e.g., CD45Rbhi T cells) obtained fromthe spleens of BALB/c mice into immunodeficient recipient CB 17scid/scid mice. Mice develop signs of redness, swelling, and skinlesions resembling those of human psoriasis in their ears, feet and tailby 8 weeks after transfer. Three groups of mice, each comprising 10-15CB.17 scid/scid mice, may be injected with purified CD45Rbhi T cells.One group of mice may additionally receive PBS and Tween 0.5% i.p. atthe initial cell transfer, and at different dosing schedules thereafter.A second group of mice may receive different doses of the CCR4antagonist(s) given either i.p., IV, SC, IM, PO or via any other mode ofadministration at the initial cell transfer, and at different dosingschedules thereafter. A third group of mice, serving as positivecontrol, may consist of mice treated with antibodies to either IL-12,IL-4, IFNγ, or TNF, or with cytokine IL-10 at the initial cell transfer,and at different dosing schedules thereafter. Animals may be monitoredfor development of psoriatic-like lesions for 3 months after celltransfer.

Inflammatory Bowel Disease. Several murine models of IBD (e.g., Crohn'sdisease and ulcerative colitis) have been developed. Some of the modelsoccur in genetically engineered transgenic mice that have been depletedof certain cytokine genes (e.g., IL-10 or IL-2) by homologousrecombination. A particular murine model of IBD is obtained bytransferring highly purified populations of CD4+T lymphocytes bearingthe surface marker phenotype cd45rb hi into

SCID mice.

Representative procedures for evaluating the efficacy of CCR4antagonists for treatment of inflammatory bowel disease comprise threegroups of mice from any of the aforementioned models. One group of micemay receive PBS and Tween 0.5% i.p. soon after weaning in the case ofthe spontaneous models in transgenic mice, or at the time of celltransfer into SCID mice and varying dosings thereafter for the celltransfer model. A second group of mice may receive different doses ofthe CCR4 antagonist(s) given either i.p., IV, SC, IM, PO or via anyother mode of administration soon after weaning in the case of thespontaneous models in transgenic mice, or at the time of cell transferinto SCID mice and varying dosings thereafter for the cell transfermodel. A third group of mice, serving as positive control, may comprisemice treated with antibodies to either IFNγ or TNF, or with the cytokineIL-10 soon after weaning in the case of the spontaneous models intransgenic mice, or at the time of cell transfer into SCID mice andvarying dosings thereafter for the cell transfer model. Mice may beevaluated for 6-8 weeks for disease development, monitored initially forweight loss and/or prolapsed rectum, and subsequently for histologicalevaluation of their colons and intestinal tracts.

Although the invention has been described with reference to the aboveexamples, it will be understood that modifications and variations areencompassed within the spirit and scope of the invention. Accordingly,the invention is limited only by the following claims.

1.-33. (canceled)
 34. A method of treating a disease or disorder,wherein the disease or disorder is cancer, an immune disease ordisorder, an inflammatory disease or disorder, a cardiovascular diseaseor disorder, or a metabolic disease or disorder, comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a C—C chemokine receptor type 4 (CCR4) inhibitor, wherein theCCR4 inhibitor is of structural Formula (II):

or a pharmaceutically acceptable salt thereof, wherein: X² is CR⁹ or N;X³ is CR¹⁰ or N; n3.2,n3.3, n9 and n10 are independently an integer from0 to 4; m3.2, m3.3, m9, m10, v3.2, v3.3, v9 and v10 are independently 1or 2 z4 is 1; L: is a bond, —O—, —S—, —NR^(72B)—, —C(O)—, —C(O)O—,—S(O)—, —S(O)₂—, substituted or unsubstituted alkylene, substituted orunsubstituted heteroalkylene, substituted or unsubstitutedcycloalkylene, substituted or unsubstituted heterocycloalkylene,substituted or unsubstituted arylene, or substituted or unsubstitutedheteroarylene; R¹ is independently hydrogen, substituted orunsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R² isindependently hydrogen, substituted or unsubstituted alkyl, orsubstituted or unsubstituted heteroalkyl; R^(3.2) is hydrogen, halogen,—CX^(3.2) ₃, —CHX^(3.2) ₂, —CH₂X^(3.2), —CN, —N₃, —SO_(n3.2)R^(3.2A),—SO_(v3.2)NR^(3.2B)R^(3.2C), —NHNR^(3.2B)R^(3.2C), —ONR^(3.2B)R^(3.2)C,—NHC(O)NHNR^(3.2B)R^(3.2C), —NHC(O)NR^(3.2B)R^(3.2C), —N(O)_(m.3.2),—NR^(3.2B)R^(3.2C), —C(O)R^(3.2B), —C(O)OR^(3.2B),—C(O)NR^(3.2B)R^(3.2C), —OR^(3.2A), —NR^(3.2B)SO₂R^(3.2A),—NR^(3.2B)C(O)R^(3.2D), —NR^(3.2B)C(O)OR^(3.2D), —NR^(3.2B)OR^(3.2D),—OCX^(3.2) ₃, —OCHX^(3.2) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(3.3) is hydrogen, halogen, —CX^(3.3) ₃, —CHX^(3.3) ₂, —CH₂X^(3.3),—CN, —N₃, —SO_(n3.3)R^(3,3A), —SO_(v3.3)NR^(3.3B)R^(3.3C),—NHNR^(3.3B)R^(3.3C), —ONR^(3.3B)R^(3.3C), —NHC(O)NHNR^(3.3B)R^(3.3C),—NHC(O)NR^(3.3B)R^(3.3C), —N(O)_(m3.3), —NR^(3.3B)R^(3.3C),—C(O)R^(3.3D), —C(O)OR^(3.3D), —C(O)NR^(3.3B)R^(3.3C), —OR^(3.3A),—NR^(3.3B)SO₂R^(3.3A), —NR^(3.3B)C(O)R^(3.3D), —NR^(3.3B)C(O)OR^(3.3D),—NR^(3.3B)OR^(3.3D), —OCX^(3.3) ₃, —OCHX^(3.3) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁴ is hydrogen, —CX^(4.1) ₃, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; R⁷ is hydrogen, substituted or unsubstitutedalkyl, phenyl, —F, —OH, CH₂OH, —(CH₂)₂OH, —(CH₂)₃OH, —C(CH₃)₂OH,—CH₂SO₂NH₂, —(CH₂)₂SO₂NH₂, —CH₂C(O)NH₂, —(CH₂)₂C(O)NH₂, —(CH₂)₃C(O)NH₂,—CH₂NHSO₂CF₃, —(CH₂)₂NHSO₂CF₃, —(CH₂)₃NHSO₂CF₃, —CH₂NHSO₂CH₃,—(CH₂)₂NHSO₂CH₃, —(CH₂)₃NHSO₂CH₃, —CH₂SO₂CH₃, —(CH₂)₂SO₂CH₃, —CH₂SO₂NH₂or —(CH₂)₂SO₂NH₂ R⁹ is hydrogen, halogen, —CX^(9.1) ₃, —CHX^(9.1) ₂,—CH₂X^(9.1), —CN, —N₃, —SO_(n9)R^(9A), —SO_(v9)NR^(9B)R^(9C),—NHNR^(9B)R^(9C), —ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C),—NHC(O)NR^(9B)R^(9C), —N(O)_(m9), —NR^(9B)R^(9C), —C(O)R^(9D),—C(O)OR^(9D), —C(O)NR^(9B)R^(9C), —OR^(9A), —NR^(9B)SO₂R^(9A),—NR^(9B)C(O)R^(9D), —NR^(9B)C(O)OR^(9D), —NR^(9B)OR^(9D), —OCX^(9.1) ₃,—OCHX^(9.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹⁰ ishydrogen, halogen, —CX^(10.1) ₃, —CHX^(10.1) ₂, —CH₂X^(10.1), —CN, —N₃,—SO_(n10)R^(10A), —SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C),—ONR^(10B)R^(10C), —NHC(O)NHNR^(10B)R^(10C), —NHC(O)NR^(10B)R^(10C),—N(O)_(m10), —NR^(10B)R^(10C), —C(O)R^(10D), —C(O)NR^(10B)R^(10C),—OR^(A), —NR^(10B)SO₂R^(10A), —NR^(10B)C(O)R^(10D),—NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D), —OCX^(10.1) ₃, —OCHX^(10.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(3.2A), R^(3.2B), R^(3.2C),R^(3.2D), R^(3.3A), R^(3.3B), R^(3.3C), R^(3.3D), R^(9A), R^(9B),R^(9C), R^(9D), R^(10A), R^(10B), R^(10C) and R^(10D) are independentlyhydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —COOH, —CONH₂, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(3.2B), R^(3.2C), R^(3.3B), R^(3.3C),R^(9B), R^(9C), R^(10B) and R^(10C) substituents bonded to the samenitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; and X^(3.2), X^(3.3) and X^(4.1) are independently —Cl, —Br,—I or —F.
 35. The method of claim 34, wherein the compound hasstructural Formula (IIa):

or a pharmaceutically acceptable salt thereof.
 36. The method of claim34, wherein the compound has structural Formula (IIb):

or a pharmaceutically acceptable salt thereof.
 37. The method of claim35, wherein the compound has structural Formula (IIc):

or a pharmaceutically acceptable salt thereof.
 38. The method of claim36, wherein the compound has structural Formula (IId):

or a pharmaceutically acceptable salt thereof. 39.-40. (canceled) 41.The method of claim 34, wherein R¹ is hydrogen.
 42. The method of claim34, wherein R² is substituted or unsubstituted alkyl.
 43. (canceled) 44.The method of claim 34, wherein R⁴ is —CN,  C(O)NH₂, —CF₃ or —CH₃. 45.The method of claim 34, wherein R^(3.2) and R^(3.3) are independentlyhalogen. 46.-48. (canceled)
 49. The method of claim 34, wherein: L⁷ is abond; and R⁷ is hydrogen, substituted or unsubstituted alkyl, phenyl,—(CH₂)₂OH, —CH₂C(CH₃)₂OH, —(CH₂)₃OH, —(CH₂)₂CH(CH₃)₂OH, —(CH₂)₂SO₂NH₂,—(CH₂)₃SO₂NH₂, —(CH₂)₂CONH₂, —(CH₂)₃CONH₂, —(CH₂)₃CON(H)Me,—(CH₂)₃CON(Me)₂, —(CH₂)₂SO₂Me, —(CH₂)₃SO₂Me, —CH₂CH(OH)Me, —CH₂CO₂H,—(CH₂)₂CO₂H, —CH(CH₃)CH₂CO₂H, —(CH₂)₃CO₂H, —(CH₂)₂SO₂NHCH₃,—(CH₂)₂SO₂N(CH₃)₂, —(CH₂)₂SO₂-(N-morpholinyl), —(CH₂)₂NHCOCH₃,—(CH₂)₃NHCOCH₃, —(CH₂)₂NHCOCH(CH₃)₂, —(CH₂)₂NHSO₂CH₃, —(CH₂)₂NHSO₂CF₃,—(CH₂)₂NHSO₂NHCH(CH₃)₂, —CH₂CH(CH₃)CH₂OH (R and S), —CH(CH₃)(CH₂)₂OH,—CH₂-(2-imidazoyl), —CH₂-(4-imidazoyl), —CH₂-(3-pyrazoyl),4-tetrahydropyranyl, 3-oxetanyl, —(CH₂)₂NHCO₂Me, —(CH₂)₃NHCO₂Me. 50.(canceled)
 51. The method of claim 34, wherein the compound hasstructural Formula (IV):

or a pharmaceutically acceptable salt thereof.
 52. The method of claim34, wherein the compound has structural Formula (V):

or a pharmaceutically acceptable salt thereof. 53.-55. (canceled) 56.The method of claim 34, wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof. 57.-63. (canceled) 64.The method of claim 34, further comprising co-administering achemotherapeutic agent or anticancer agent in combination with thecompound of structural Formula (II).
 65. The method of claim 64, whereinthe chemotherapeutic agent or anticancer agent is anantiproliferative/antineoplastic drug, an antimetabolite, an antitumourantibiotic, an antimitotic agent, a topoisomerase inhibitor, acytostatic agent, an oestrogen receptor down regulator, an antiandrogen,a LHRH antagonist or LHRH agonist, a progestogen, an aromataseinhibitor, an inhibitor of 5.alpha.-reductase, an agent which inhibitscancer cell invasion, an inhibitor of growth factor function, a farnesyltransferase inhibitor, a tyrosine kinase inhibitor, a serine/threoninekinase inhibitor, an inhibitor of the epidermal growth factor family, aninhibitor of the platelet-derived growth factor family, an inhibitor ofthe hepatocyte growth factor family; an antiangiogenic agent, a vasculardamaging agent, an agent used in antisense therapy, an anti-rasantisense, an agent used in a gene therapy, an immunotherapeutic agent,or an antibody.
 66. The method of claim 65, further comprisingco-administering a therapeutically effective amount of at least two of:a CCR4 inhibitor, an inhibitor of the PD-L1/PD-1 pathway, an inhibitorof CTLA-4 or an agonistic antibody of CD137 (4-1BB).
 67. The method ofclaim 65, further comprising co-administering a therapeuticallyeffective amount of at least two of: a CCR4 inhibitor, animmunotherapeutic agent or an agent from Table 1, or any combinationthereof.
 68. The method of claim 34 or 64, wherein the cancer is coloncancer, pancreatic cancer, kidney cancer, breast cancer, lung cancer,bladder cancer, urinary bladder cancer, ovarian cancer, endometrialcancer, adrenal cortical cancer, cervical cancer, prostate cancer,stomach cancer, gastric cancer, colorectal cancer, brain cancer, headand neck cancer, skin cancer, uterine cancer, testicular cancer, glioma,esophagus cancer, esophageal cancer, liver cancer, genitourinary tractcancer, lymphoma, leukemia, cancer of the thyroid, medullary thyroidcancer, papillary thyroid cancer, or cancer of the endocrine system. 69.The method of claim 68, wherein the cancer is hepatocarcinoma, B-acutelymphoblastic lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma,Small Cell lymphoma, Large Cell lymphomas, classical Hodgkin's lymphoma,MDS, AML, ALL, ATLL, CML, multiple myeloma, glioblastoma, neuroblastoma,non-small cell lung cancer, melanoma, mesothelioma, medulloblastoma,thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, skincutaneous melanoma, colon adenocarcinoma, rectum adenocarcinoma, stomachadenocarcinoma, esophageal carcinoma, head and neck squamous cellcarcinoma, breast invasive carcinoma, triple-negative breast cancer,lung adenocarcinoma, lung squamous cell carcinoma, Hodgkin's Disease,neuroblastoma, glioblastoma multiforme, rhabdomyosarcoma, primary braintumos, malignant pancreatic insulanoma, malignant carcinoid,premalignant skin lesions, neuroblastoma, malignant hypercalcemia,neoplasms of the endocrine or exocrine pancreas, medullary thyroidcarcinoma, melanoma, or hepatocellular carcinoma.
 70. . The method ofclaim 34, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 71. The method of claim34, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 72. The method of claim34, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 73. The method of claim34, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 74. The method of claim34, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 75. The method of claim34, wherein the compound is:

or a pharmaceutically acceptable salt thereof.